Bicyclic heteroaryl inhibitors of pde4

ABSTRACT

The present invention relates to compounds and methods which may be useful as inhibitors of phosphodiesterase 4 (PDE4) for the treatment or prevention of inflammatory diseases and other diseases involving elevated levels of cytokines and proinflammatory mediators.

This application is a continuation-in-part of U.S. application Ser. No.11/774,053, filed Jul. 6, 2007, which claims priority to U.S.Provisional Application No. 60/819,509, filed Jul. 7, 2006, and No.60/886,825, filed Jan. 26, 2007, the disclosures of which are herebyincorporated by reference as if written herein in its entirety.

Disclosed herein are new bicyclic heteroaryl compounds and compositionsand their application as pharmaceuticals for the treatment of disease.Methods of inhibition of phosphodiesterase 4 (PDE4) activity in a humanor animal subject are also provided for the treatment diseases such asinflammatory diseases and other diseases involving elevated levels ofcytokines and proinflammatory mediators.

Chronic inflammation is a multi-factorial disease complicationcharacterized by activation of multiple types of inflammatory cells, forexample cells of lymphoid lineage (including T lymphocytes) and myeloidlineage (including granulocytes, macrophages, and monocytes).Proinflammatory mediators, including cytokines, such as tumor necrosisfactor (TNF) and interleukin-1 (IL-1), are produced by these activatedcells. Accordingly, an agent that suppresses the activation of thesecells, or their production of proinflammatory cytokines, would be usefulin the therapeutic treatment of inflammatory diseases and other diseasesinvolving elevated levels of cytokines

Cyclic adenosine monophosphate (cAMP) is a second messenger thatmediates the biologic responses of cells to a wide range ofextracellular stimuli. When the appropriate agonist binds to specificcell surface receptors, adenylate cyclase is activated to convertadenosine triphosphate (ATP) to cAMP. It is theorized that the agonistinduced actions of cAMP within the cell are mediated predominately bythe action of cAMP-dependent protein kinases. The intracellular actionsof cAMP are terminated by either a transport of the nucleotide to theoutside of the cell, or by enzymatic cleavage by cyclic nucleotidephosphodiesterases (PDEs), which hydrolyze the 3′-phosphodiester bond toform 5′-adenosine monophosphate (5′-AMP). 5′-AMP is an inactivemetabolite.

The superfamily of PDEs is subdivided into two major classes, class Iand class II, which have no recognizable sequence similarity. Class Iincludes all known mammalian PDEs and is comprised of 11 identifiedfamilies that are products of separate genes. Some PDEs are highlyspecific for hydrolysis of cAMP (PDE4, PDE7, PDE8), some are highlycGMP-specific (PDE5, PDE6, PDE9), and some have mixed specificity (PDE1,PDE2, PDE3, PDE10, PDE11). All of the characterized mammalian PDEs aredimeric, but the importance of the dimeric structure for function ineach of the PDEs is unknown.

The PDE4 subfamily is comprised of 4 members: PDE4A, PDE4B, PDE4C, andPDE4D. These enzymes possess N-terminal regulatory domains thatpresumably mediate dimerization, which results in optimally regulatedPDE activity. In addition, activity is regulated via cAMP-dependentprotein kinase phosphorylation sites in this upstream regulatory domain.PDE4 enzymes are broadly expressed and distributed.

Elevated levels of cAMP in human myeloid and lymphoid lineage cells areassociated with the suppression of cell activation. The intracellularenzyme family of PDEs, therefore, regulates the level of cAMP in cells.PDE4 is a predominant PDE isotype in these cells, and is a majorcontributor to cAMP degradation. Accordingly, the inhibition of PDEfunction would prevent the conversion of cAMP to the inactive metabolite5′-AMP and, consequently, maintain higher cAMP levels, and, accordingly,suppress cell activation.

PDE4 inhibitors have been shown to inhibit production of TNFα andpartially inhibit IL-1β release by monocytes (see Semmler et al., Int.J. Immunopharmacol., 15, pp. 409-413, (1993); Molnar-Kimber et al.,Mediators of Inflammation, 1, pp. 411-417, (1992)). PDE4 inhibitors alsohave been shown to inhibit the production of superoxide radicals fromhuman polymorphonuclear leukocytes (see Verghese et al., J. Mol. Cell.Cardiol., 21 (Suppl. 2), S61 (1989); Nielson et al., J. AllergyImmunol., 86, pp. 801-808, (1990)); to inhibit the release of vasoactiveamines and prostanoids from human basophils (see Peachell et al., J.Immunol., 148, pp. 2503-2510, (1992)); to inhibit respiratory bursts ineosinophils (see Dent et al., J. Pharmacol., 103, pp. 1339-1346,(1991)); and to inhibit the activation of human T-lymphocytes (seeRobicsek et al., Biochem. Pharmacol., 42, pp. 869-877, (1991)).

Inflammatory cell activation and excessive or unregulated cytokine(e.g., TNFα and IL-1β) production are implicated in allergic,autoimmune, and inflammatory diseases and disorders, such as rheumatoidarthritis, osteoarthritis, gouty arthritis, spondylitis, thyroidassociated ophthalmopathy, Behcet's disease, sepsis, septic shock,endotoxic shock, gram negative sepsis, gram positive sepsis, toxic shocksyndrome, asthma, chronic bronchitis, adult respiratory distresssyndrome, chronic pulmonary inflammatory disease, such as chronicobstructive pulmonary disease, silicosis, pulmonary sarcoidosis,reperfusion injury of the myocardium, brain, and extremities, fibrosis,cystic fibrosis, keloid formation, scar formation, atherosclerosis,transplant rejection disorders, such as graft vs. host reaction andallograft rejection, chronic glomerulonephritis, lupus, inflammatorybowel disease, such as Crohn's disease and ulcerative colitis,proliferative lymphocyte diseases, such as leukemia, ophthalmologicdiseases such as dry eye and ocular pain resulting from inflammation orsurgery, and inflammatory dermatoses, such as atopic dermatitis,psoriasis, and urticaria.

Other conditions characterized by elevated cytokine levels include braininjury due to moderate trauma, cardiomyopathies, such as congestiveheart failure, cachexia, cachexia secondary to infection or malignancy,cachexia secondary to acquired immune deficiency syndrome (AIDS), ARC(AIDS related complex), fever myalgias due to infection, cerebralmalaria, osteoporosis and bone resorption diseases, keloid formation,scar tissue formation, and pyrexia.

Additionally, several properties of TNFα, such as stimulation ofcollagenases, stimulation of angiogenesis in vivo, stimulation of boneresorption, and an ability to increase the adherence of tumor cells toendothelium, are consistent with a role for TNF in the development andmetastatic spread of cancer in the host. TNFα recently has been directlyimplicated in the promotion of growth and metastasis of tumor cells (seeOrosz et al., J. Exp. Med., 177, pp. 1391-1398, (1993)).

Investigators have shown considerable interest in the use of PDE4inhibitors as anti-inflammatory agents. Early evidence indicates thatPDE4 inhibition has beneficial effects on a variety of inflammatorycells such as monocytes, macrophages, T-cells of the Th-1 lineage, andgranulocytes. The synthesis and/or release of many proinflammatorymediators, such as cytokines, lipid mediators, superoxide, and biogenicamines, such as histamine, have been attenuated in these cells by theaction of PDE4 inhibitors. The PDE4 inhibitors also affect othercellular functions including T-cell proliferation, granulocytetransmigration in response to chemotoxic substances, and integrity ofendothelial cell junctions within the vasculature.

The design, synthesis, and screening of various PDE4 inhibitors havebeen reported. Methylxanthines, such as caffeine and theophylline, werethe first PDE inhibitors discovered, but these compounds arenonselective with respect to which PDE is inhibited. The drug rolipram,an antidepressant agent, was one of the first reported specific PDE4inhibitors, with a reported IC₅₀ of about 200 nM with respect toinhibiting recombinant human PDE4.

Investigators have continued to search for PDE4 inhibitors that are moreselective with respect to inhibiting PDE4, that have a lower IC₅₀ thanrolipram, and that avoid the undesirable central nervous system (CNS)side effects, such as retching, vomiting, and sedation, associated withthe administration of rolipram. In addition, several companies are nowundertaking clinical trials of other PDE4 inhibitors. However, problemsrelating to efficacy and adverse side effects, such as emesis andcentral nervous system disturbances, remain unsolved.

Accordingly, compounds that selectively inhibit PDE4, and that reduce oreliminate the adverse side effects associated with prior PDE4inhibitors, would be useful in the treatment of allergic andinflammatory diseases, and other diseases associated with excessive orunregulated production of cytokines, such as TNF. In addition, selectivePDE4 inhibitors would be useful in the treatment of diseases that wouldbenefit from elevated cAMP levels or reduced PDE4 function in aparticular target tissue.

Novel compounds and pharmaceutical compositions, certain of which havebeen found to inhibit PDE4 have been discovered, together with methodsof synthesizing and using the compounds including methods for thetreatment of PDE4—mediated diseases in a patient by administering thecompounds.

In certain embodiments of the present invention, compounds havestructural Formula I:

wherein:

A is an optionally substituted saturated or unsaturated hydrocarbonchain or a heteroatom-comprising hydrocarbon chain having from 3 to 5atoms, forming a five- to seven-membered ring;

U, and V are independently selected from the group consisting of O,N(R⁷) and SO_(q);

R¹ and R² independently selected from the group consisting of hydrogen,—(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy,alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted;

s is 0-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, alkoxy and lower alkyl;

R⁵ is selected from the group consisting of —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)—and —(CR¹²R¹³)_(p)—;

m, n, and q are each independently 0, 1 or 2;

p is 1 or 2;

W is selected from the group consisting of O, N(R⁷), C(O)N(R⁷), andSO_(q);

R⁶ is selected from the group consisting of carboxy, alkylcarboxy,amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,heteroalkyl, acyl, and hydroxamic acid, any of which may be optionallysubstituted;

R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independently selected fromthe group consisting of hydrogen, halogen, hydroxyl, lower alkyl,hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl, andaminoalkoxy; and hydrogen and optionally substituted lower alkyl.

Certain compounds disclosed herein may possess useful PDE4 inhibitingactivity, and may be used in the treatment or prophylaxis of a diseaseor condition in which PDE4 plays an active role. Thus, in broad aspect,certain embodiments also provide pharmaceutical compositions comprisingone or more compounds disclosed herein together with a pharmaceuticallyacceptable carrier, as well as methods of making and using the compoundsand compositions. Certain embodiments provide methods for inhibitingPDE4. Other embodiments provide methods for treating a PDE4-mediateddisorder in a patient in need of such treatment, comprisingadministering to said patient a therapeutically effective amount of acompound or composition according to the present invention. Relatedembodiments disclose the use of certain compounds disclosed herein astherapeutic agents, for example, in treating inflammatory diseases andother diseases involving elevated levels of cytokines andproinflammatory mediators. Also provided is the use of certain compoundsdisclosed herein for use in the manufacture of a medicament for thetreatment of a disease or condition ameliorated by the inhibition ofPDE4.

In certain embodiments, the compounds have structural Formula II:

wherein:

X¹ is NR¹⁴;

X² is selected from the group consisting of C(O), (CR¹⁵ R¹⁶) and null;

X³ is selected from the group consisting of C(O), N(R¹⁷) and (CR¹⁸R¹⁹);

R¹ and R² are independently selected from the group consisting ofhydrogen, —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl,alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted;

s is 0-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, halogen, alkoxy and lower alkyl;

R⁵ is selected from the group consisting of —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)—and —(CR¹²R¹³)_(p)—;

m, n, and q are each independently 0, 1 or 2;

p is 1 or 2;

W is selected from the group consisting of O, N(R⁷), C(O)N(R⁷), andSO_(q);

R⁶ is selected from the group consisting of carboxy, alkylcarboxy,amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,heteroalkyl, acyl, and hydroxamic acid, any of which may be optionallysubstituted;

R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from thegroup consisting of hydrogen and optionally substituted lower alkyl;

R¹⁴ and R¹⁷ are each independently selected from the group consisting ofhydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, haloalkyl,aminoalkyl, and a bond; and

R¹⁵, R¹⁶, R¹⁸, and R¹⁹ are each independently selected from the groupconsisting of hydrogen, halogen, lower alkyl, haloalkyl, alkoxy,haloalkoxy, amino, aminoalkyl, aminoalkoxy, and null.

In certain further embodiments, compounds of the present invention havestructural formula III

wherein:

X¹ is NR¹⁴;

X² is selected from the group consisting of C(O) and null;

X³ is selected from the group consisting of C(O) and (CR¹⁸R¹⁹);

R¹ and R² are independently selected from the group consisting ofhydrogen, —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl,alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl,alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted;

s is 1-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, halogen, alkoxy and lower alkyl;

R⁵ is selected from the group consisting of —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)—and —(CR¹²R¹³)_(p)—;

m, n, and q are each independently 0, 1 or 2;

p is 1 or 2;

W is selected from the group consisting of O, N(R⁷), C(O)N(R⁷), andSO_(q);

R⁶ is selected from the group consisting of carboxyl, alkylcarboxy,amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,heteroalkyl, acyl, and hydroxamic acid, any of which may be optionallysubstituted;

R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from thegroup consisting of hydrogen and optionally substituted lower alkyl;

R⁷ and R¹⁴ are independently selected from the group consisting ofhydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, haloalkyl, andaminoalkyl; and

R¹⁵and R¹⁶ are each independently selected from the group consisting ofhydrogen, halogen, lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino,aminoalkyl, aminoalkoxy, and null.

In certain embodiments, compounds of the present invention havestructural Formula IV

wherein:

X³ is (CR¹⁸R¹⁹);

R¹ and R² are independently selected from the group consisting ofhydrogen, —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl,alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl,alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted;

s is 1-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, halogen, alkoxy, and lower alkyl;

R⁵ is selected from the group consisting of —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)—and —(CR¹²R¹³)_(p)—;

m, n, and q are each independently 0, 1 or 2;

p is 1 or 2;

W is selected from the group consisting of O, N(R⁷), C(O)N(R⁷), andSO_(q);

R⁶ is selected from the group consisting of carboxyl, alkylcarboxy,amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,heteroalkyl, acyl, and hydroxamic acid, any of which may be optionallysubstituted;

R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independently selected from thegroup consisting of hydrogen and optionally substituted lower alkyl;

R⁷ and R¹⁴ are independently selected from the group consisting ofhydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, haloalkyl, andaminoalkyl; and

R¹⁸ and R¹⁹ are each independently selected from the group consisting ofhydrogen, halogen, lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino,aminoalkyl, aminoalkoxy, and a null.

In further embodiments, compounds of the present invention havestructural Formula V

wherein:

R¹ and R² are independently selected from the group consisting ofhydrogen, —(CH₂),G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl,alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl,alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted;

s is 1-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted;

R⁵ is selected from the group consisting of —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹⁾ _(n)—and —(CR¹²R¹³)_(p)—;

m, n, and q are each independently 0, 1 or 2;

p is 1 or 2;

W is selected from the group consisting of O, N(R⁷), C(O)N(R⁷), andSO_(q);

R⁶ is selected from the group consisting of carboxyl, alkylcarboxy,amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,heteroalkyl, acyl, and hydroxamic acid, any of which may be optionallysubstituted;

R⁷ and R¹⁴ are independently selected from the group consisting ofhydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, haloalkyl, andaminoalkyl; and

R¹⁹ is selected from the group consisting of hydrogen, halogen, loweralkyl and haloalkyl.

In yet further embodiments are provided compounds wherein R⁷ and R¹⁴ areindependently selected from the group consisting of hydrogen, halogenand optionally substituted lower alkyl

In yet further embodiments are provided compounds wherein R⁶ is selectedfrom the group consisting of aryl and heteroaryl, either of which may beoptionally substituted;

In yet further embodiments are provided compounds wherein R¹⁹ ishydrogen.

In yet further embodiments are provided compounds wherein R⁶ is selectedfrom the group consisting of phenyl, pyridine, pyrimidine, pyridazine,and pyrazine, any of which may be optionally substituted.

In yet further embodiments are provided compounds wherein R⁶ is selectedfrom the group consisting of phenyl, pyridine, and pyrimidine, any ofwhich may be optionally substituted.

In yet further embodiments are provided compounds wherein R¹⁴ ishydrogen.

In yet further embodiments are provided compounds wherein:

R⁵ is —(CR⁸R⁹)_(m)W(CR¹⁰R¹¹)_(n)—;

m and n are both 0;

W is N(R⁷); and

R⁷ is hydrogen.

In yet further embodiments are provided compounds wherein R⁶ has theformula

wherein:

X⁴ is CR²⁰ or N;

X⁵ is CR²¹ or N;

X⁶ is CR²² or N;

X⁷ is CR²³ or N;

X⁸ is CR²⁴ or N;

wherein no more than two of X⁴—X⁸ may be N; and

R²⁰, R²¹, R²², R²³ and R²⁴ are independently selected from the groupconsisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy,lower haloalkyl, lower haloalkoxy, amino, and carboxyl.

In yet further embodiments are provided compounds wherein R⁶ has aformula selected from the group consisting of

In certain embodiments are provided compounds wherein R² is lower alkyl.

In further embodiments, R² is methyl.

In yet further embodiments are provided compounds wherein:

R¹ is selected from the group consisting of —(CH₂)_(s)G¹G²G³, loweralkyl, cycloalkyl, cycloalkylalkyl, and heterocycloalkyl, any of whichmay be optionally substituted;

s is 1-6;

G¹ is selected from the group consisting of amino, amido, and null;

G² is selected from the group consisting of alkoxy, aryl, halo,heterocycloalkyl, and null, any of which may be optionally substituted;and

G³ is selected from the group consisting of alkyl, carboxyl, and null,any of which may be optionally substituted.

In further embodiments, compounds of the present invention havestructural Formula VI

wherein:

R¹ and R² are independently selected from the group consisting ofhydrogen, —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl,alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl,alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, heteroaryl, heteroaralkyl, hydrogen and hydroxyalkyl, anyof which may be optionally substituted;

s is 1-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted; and

R²⁰ and R²⁴ are independently selected from the group consisting ofhydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl,lower haloalkoxy, amino, and carboxyl.

In certain embodiments, R²⁰ and R²⁴ are independently selected from thegroup consisting of hydrogen, halogen, and lower alkyl.

In certain embodiments are provided compounds wherein:

R¹ and R² are independently selected from the group consisting of—(CH₂)_(s)G¹G²G³, acyl, acylalkyl, C₁-C₁₀ alkyl, aminoalkyl, alkenyl,alkynyl, carboxyalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, heteroaryl, andheteroaralkyl, any of which maybe optionally substituted; and

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, heterocycloalkyl, heteroaryl, carboxylalkylamino, an amino acid,and null, any of which may be optionally substituted with a substituentselected from the group consisting of lower alkyl, amino, alkylamino,aminoalkylamino, hydroxyalkylamino, cycloalkyl, and heterocycloalkyl

In other embodiments, R²⁰ and R²⁴ are independently selected from thegroup consisting of halogen and lower alkyl.

In certain embodiments, R² is lower alkyl.

In further embodiments are provided compounds wherein:

R¹ is selected from the group consisting of —(CH₂)_(s)G¹G²G³, loweralkyl, cycloalkyl, cycloalkylalkyl, and heterocycloalkyl, any of whichmay be optionally substituted;

s is 1-6;

G¹ is selected from the group consisting of amino, amido, and null;

G² is selected from the group consisting of alkoxy, amino, aryl, halo,heterocycloalkyl, and null, any of which may be optionally substituted;and

G³ is selected from the group consisting of alkyl, carboxyl, and null,any of which may be optionally substituted.

In further embodiments, R² is methyl.

In yet further embodiments, R^(l) is —(CH₂)_(s)G².

In certain embodiments, s is 6.

In other embodiments, R²⁰ and R²⁴ are independently selected from thegroup consisting of halogen and methyl.

In yet other embodiments, R²⁰ and R²⁴ are independently selected fromthe group consisting of chlorine and methyl.

In further embodiments, G² is selected from the group consisting ofamino and heterocycloalkyl.

In further embodiments, G² is selected from the group consisting of afive-, six-, and seven-membered heterocycloalkyl containing one or twonitrogens.

In yet further embodiments, G² has a formula selected from the groupconsisting of

t is 1 or 2;

w is 0 or 1;

R²⁵ and R²⁶ are independently selected from the group consisting ofhydrogen, methyl, —(CH₂)_(x)OH, and —(CH₂)₃N(CH₃)₂;

x is 2 or 3; and

R²⁷ is selected from the group consisting of hydrogen and methyl.

In yet further embodiments, G² has a formula selected from the groupconsisting of

R²⁵ and R²⁶ are independently selected from the group consisting ofmethyl and —(CH₂)_(x)OH.

In certain embodiments, R²⁰ and R²⁴ are each chlorine.

In other embodiments, G² has the formula

In certain embodiments are provided compounds wherein R²⁷ is methyl.

In other embodiments, t is 1.

In yet other embodiments, t is 2.

In further embodiments, G² has the formula selected from the groupconsisting of

In certain embodiments, G² has the formula

In certain embodiments, G² is —NR²⁵R²⁶.

In other embodiments

R²⁵ is methyl; and

R²⁶ is and —(CH₂)_(x)OH.

In yet other embodiments, x is 2.

In further embodiments, R²⁵ and R²⁶ are each methyl.

In further embodiments, R²⁰ and R²⁴ are each methyl.

In certain embodiments, compounds of the present invention havestructural Formula VII

wherein:

R¹ and R² are independently selected from the group consisting ofhydrogen, —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl, cyanoalkyl,alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl,alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen andhydroxyalkyl, any of which may be optionally substituted;

s is 1-8;

G¹ is selected from the group consisting of alkoxy, amino, amido,carbonyl, hydroxy, ether, an amino acid, and null;

G² is selected from the group consisting of alkyl, alkoxy, amino, aryl,halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,guanidine, an amino acid, and null, any of which may be optionallysubstituted;

G³ is selected from the group consisting of alkyl, alkoxy, amino,hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoamide, and null, any of which may be optionally substituted; and

R²⁰, R²², and R²⁴ are independently selected from the group consistingof hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lowerhaloalkyl, lower haloalkoxy, amino, and carboxyl.

Compounds of the present invention may be selective amongst the PDE4isoforms PDE4A, PDE4B, PDE4C, and PDE4D in various ways. For example,compounds described herein may be selective for PDE4B and PDE4D over theother two isoforms, be a pan-inhibitor of all the isoforms, or beselective for only one isoform. In certain embodiments, compounds of thepresent invention may be selective for PDE4B over other isoforms.

The present invention also relates to a method of inhibiting at leastone PDE4 function comprising the step of contacting the PDE4 with acompound of Formula I, as described herein. The cell phenotype, cellproliferation, activity of PDE4, change in biochemical output producedby active PDE4, expression of PDE4, or binding of PDE4 with a naturalbinding partner may be monitored. Such methods may be modes of treatmentof disease, biological assays, cellular assays, biochemical assays, orthe like.

As used herein, the terms below have the meanings indicated.

When ranges of values are disclosed, and the notation “from n₁ . . . ton₂” or “between n₁ . . . and n₂” is used, where n₁ and n₂ are thenumbers, then unless otherwise specified, this notation is intended toinclude the numbers themselves and the range between them. This rangemay be integral or continuous between and including the end values. Byway of example, the range “from 2 to 6 carbons” is intended to includetwo, three, four, five, and six carbons, since carbons come in integerunits. Compare, by way of example, the range “from 1 to 3 μM(micromolar),” which is intended to include 1 μM, 3 μM, and everythingin between to any number of significant figures (e.g., 1.255 μM, 2.1 μM,2.9999 μM, etc.). When n is set at 0 in the context of “0 carbon atoms”,it is intended to indicate a bond or null.

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety where the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. An“alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Examples of suchgroups include methylcarbonyl and ethylcarbonyl. Examples of acyl groupsinclude formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon group having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [(—CH═CH—),(—C::C—)].Examples of suitable alkenyl groups include ethenyl, propenyl,2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwisespecified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether group, wherein the term alkyl is as defined below. Examplesof suitable alkyl ether groups include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl group containing from 1 to 20carbon atoms. In certain embodiments, said alkyl will comprise from 1 to10 carbon atoms. In further embodiments, said alkyl will comprise from 1to 6 carbon atoms. Alkyl groups may be optionally substituted as definedherein. Examples of alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, noyl and the like. The term “alkylene,” as used herein,alone or in combination, refers to a saturated aliphatic group derivedfrom a straight or branched chain saturated hydrocarbon attached at twoor more positions, such as methylene (—CH₂—). Unless otherwisespecified, the term “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) group wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether groups include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon group having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C:::C—, —C≡C—). Examples of alkynylgroups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.Unless otherwise specified, the term “alkynyl” may include “alkynylene”groups.

The terms “amido” and “carbamoyl,”as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C-amido” as used herein, alone or in combination, refers to a-C(=O)-NR₂ group with R as defined herein. The term “N-amido” as usedherein, alone or in combination, refers to a RC(═O)NH— group, with R asdefined herein. The term “acylamino” as used herein, alone or incombination, embraces an acyl group attached to the parent moietythrough an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, alkyl, hydroxyalkyl, acyl, heteroalkyl, aryl,cycloalkyl, heteroaryl, and heterocycloalkyl, any of which maythemselves be optionally substituted. Additionally, R and R′ may combineto form heterocycloalkyl, either of which may be optionally substituted.

The term “amino acid”, as used herein, alone or in combination, refersto a —NHCHRC(O)O— group, which may be attached to the parent molecularmoiety to give either an N-terminus or C-terminus amino acid, wherein Ris independently selected from the group consisting of hydrogen, alkyl,aryl, heteroaryl, heterocycloalkyl, aminoalkyl, amido, amidoalkyl,carboxyl, carboxylalkyl, guanidinealkyl, hydroxyl, thiol, and thioalkyl,any of which themselves may be optionally substituted. The termC-terminus, as used herein, alone or in combination, refers to theparent molecular moiety being bound to the amino acid at the aminogroup, to give an amide as described herein, with the carboxyl groupunbound, resulting in a terminal carboxyl group, or the correspondingcarboxylate anion. The term N-terminus, as used herein, alone or incombination, refers to the parent molecular moiety being bound to theamino acid at the carboxyl group, to give an ester as described herein,with the amino group unbound resulting in a terminal secondary amine, orthe corresponding ammonium cation. In other words, C-terminus refers to—NHCHRC(O)OH or to —NHCHRC(O)O⁻ and N-terminus refers to H₂NCHRC(O)O— orto H₃N⁺CHRC(O)O—.

The term “aryl”, as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,”as used herein, aloneor in combination, refers to an acyl group derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, naphthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent group C₆H₄═ derived from benzene. Examples includebenzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which may beoptionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NRR′ group, with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O-carboxy” group refers to a RC(O)O— group, where R is asdefined herein. A “C-carboxy” group refers to a —C(O)OR groups where Ris as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moietycontains from 3 to 12 carbon atom ring members and which may optionallybe a benzo fused ring system which is optionally substituted as definedherein. In certain embodiments, said cycloalkyl will comprise from 5 to7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and thelike. “Bicyclic” and “tricyclic” as used herein are intended to includeboth fused ring systems, such as decahydronaphthalene,octahydronaphthalene as well as the multicyclic (multicentered)saturated or partially unsaturated type. The latter type of isomer isexemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane,and bicyclo[3,2,1]octane.

The term “ester,” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “guanidine”, as used herein, alone or in combination, refers to—NHC(═NH)NH₂, or the corresponding guanidinium cation.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl group having the meaning as defined above wherein one or morehydrogen atoms are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkylgroup, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the group. Dihalo and polyhaloalkyl groups may have two or moreof the same halo atoms or a combination of different halo groups.Examples of haloalkyl groups include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon group, orcombinations thereof, fully saturated or containing from 1 to 3 degreesof unsaturation, consisting of the stated number of carbon atoms andfrom one to three heteroatoms selected from the group consisting of O,N, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N and S may be placed at any interior position of theheteroalkyl group. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃.

The term “heteroaryl,” as used herein, alone or in combination, refersto a 3 to 7 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom selectedfrom the group consisting of O, S, and N. In certain embodiments, saidheteroaryl will comprise from 5 to 7 carbon atoms. The term alsoembraces fused polycyclic groups wherein heterocyclic rings are fusedwith aryl rings, wherein heteroaryl rings are fused with otherheteroaryl rings, wherein heteroaryl rings are fused withheterocycloalkyl rings, or wherein heteroaryl rings are fused withcycloalkyl rings. Examples of heteroaryl groups include pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl,benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl,tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl,thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplarytricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyland the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated monocyclic, bicyclic, ortricyclic heterocyclic group containing at least one heteroatom as aring member, wherein each said heteroatom may be independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur In certainembodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatomsas ring members. In further embodiments, said hetercycloalkyl willcomprise from 1 to 2 heteroatoms as ring members. In certainembodiments, said hetercycloalkyl will comprise from 3 to 8 ring membersin each ring. In further embodiments, said hetercycloalkyl will comprisefrom 3 to 7 ring members in each ring. In yet further embodiments, saidhetercycloalkyl will comprise from 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sulfones,sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclicfused and benzo fused ring systems; additionally, both terms alsoinclude systems where a heterocycle ring is fused to an aryl group, asdefined herein, or an additional heterocycle group. Examples ofheterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl,dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl,dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl,benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl,methylpiperazinyl, N-methylpiperazinyl, pyrrolidinyl,tetrahydropyridinyl, piperidinyl, thiomorpholinyl, diazepanyl, and thelike. The heterocycle groups may be optionally substituted unlessspecifically prohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “hydroxamic acid”, as used herein, alone or in combination,refers to —C(═O)NHOH, wherein the parent molecular moiety is attached tothe hydroxamic acid group by means of the carbon atom.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous oradjacent chain of carbon atoms starting at the point of attachment of agroup to the compounds of any one of the formulas disclosed herein.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower,” as used herein, alone or in a combination, where nototherwise specifically defined, means containing from 1 to and including6 carbon atoms.

The term “lower aryl,” as used herein, alone or in combination, meansphenyl or naphthyl, which may be optionally substituted as provided.

The term “lower heteroaryl,” as used herein, alone or in combination,means either 1) monocyclic heteroaryl comprising five or six ringmembers, of which between one and four said members may be heteroatomsselected from the group consisting of O, S, and N, or 2) bicyclicheteroaryl, wherein each of the fused rings comprises five or six ringmembers, comprising between them one to four heteroatoms selected fromthe group consisting of O, S, and N.

The term “lower cycloalkyl,” as used herein, alone or in combination,means a monocyclic cycloalkyl having between three and six ring members.Lower cycloalkyls may be unsaturated. Examples of lower cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or incombination, means a monocyclic heterocycloalkyl having between threeand six ring members, of which between one and four may be heteroatomsselected from the group consisting of O, S, and N. Examples of lowerheterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls maybe unsaturated.

The term “lower amino,” as used herein, alone or in combination, refersto —NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, lower alkyl, and lower heteroalkyl, any of whichmay be optionally substituted. Additionally, the R and R′ of a loweramino group may combine to form a five- or six-memberedheterocycloalkyl, either of which may be optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The term “phosphonate,” as used herein, alone or in combination, refersto a —P(═O)(OR)₂ group, wherein R is selected from the group consistingof alkyl and aryl. The term “phosphonic acid”, as used herein, alone orin combination, refers to a —P(═O)(OH)₂ group.

The term “phosphoramide”, as used herein, alone or in combination,refers to a —P(═O)(NR)₃ group, with R as defined herein.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer to the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NR′— group with R and R′ asdefined herein.

The term “S-sulfonamido” refers to a —S(═O)₂NRR′, group, with R and R′as defined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′as defined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ asdefined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said groupis absent. When any one or more of G¹, G², and G³ of —(CH₂)_(s)G¹G²G³ isdesignated to be “null”, said group condenses to either a bond if itoccupies an interior position (as with G¹ and G²), or is absent if itoccupies a terminal position (as with G³). Thus, for example, if G¹ andG³ are both null, then —(CH₂)_(s)G¹G²G³ condenses to —(CH₂),_(s)G². IfG² and G³ are both null, then —(CH₂)_(s)G¹G²G³ condenses to—(CH₂)_(s)G¹. Similarly, if G¹ and G² are both null, then—(CH₂)_(s)G¹G²G³ condenses to —(CH₂)_(s)G³. When s is designated to be0, then the (CH₂)_(s) portion of —(CH₂)_(s)G¹G²G³ collapses to a bondconnecting o to G¹G²G³. Each of G¹, G², and G³ are not meant to be nullsimultaneously and only two of G¹, G², and G³ may be null at once.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Twosubstituents may be joined together to form a fused five-, six-, orseven-membered carbocyclic or heterocyclic ring consisting of zero tothree heteroatoms, for example forming methylenedioxy or ethylenedioxy.An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃),fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl,heteroaryl and heterocycloalkyl, any of which may be optionallysubstituted. Such R and R′ groups should be understood to be optionallysubstituted as defined herein. Whether an R group has a numberdesignation or not, every R group, including R, R′ and R^(n) where n=(1,2, 3, . . . n), every substituent, and every term should be understoodto be independent of every other in terms of selection from a group.Should any variable, substituent, or term (e.g. aryl, heterocycle, R,etc.) occur more than one time in a formula or generic structure, itsdefinition at each occurrence is independent of the definition at everyother occurrence. Those of skill in the art will further recognize thatcertain groups may be attached to a parent molecule or may occupy aposition in a chain of elements from either end as written. Thus, by wayof example only, an unsymmetrical group such as —C(O)N(R)— may beattached to the parent moiety at either the carbon or the nitrogen.

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as d-isomers and l-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentinvention includes all cis, trans, syn, anti, entgegen (E), and zusammen(Z) isomers as well as the appropriate mixtures thereof. Additionally,compounds may exist as tautomers; all tautomeric isomers are provided bythis invention. Additionally, the compounds disclosed herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder” and“condition” (as in medical condition), in that all reflect an abnormalcondition of the human or animal body or of one of its parts thatimpairs normal functioning, is typically manifested by distinguishingsigns and symptoms, and causes the human or animal to have a reducedduration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

“PDE4 inhibitor” is used herein to refer to a compound that exhibits anIC₅₀ with respect to PDE4 activity of no more than about 100 μM and moretypically not more than about 50 μM, as measured in the PDE4 assaydescribed generally hereinbelow. “IC₅₀” is that concentration ofinhibitor which reduces the activity of an enzyme (e.g., PDE4) tohalf-maximal level. Certain representative compounds of the presentinvention have been discovered to exhibit inhibition against PDE4. Incertain embodiments, compounds will exhibit an IC₅₀ with respect to PDE4of no more than about 10 μM; in further embodiments, compounds willexhibit an IC₅₀ with respect to PDE4 of no more than about 5 μM; in yetfurther embodiments, compounds will exhibit an IC₅₀ with respect to PDE4of not more than about 1 μM, as measured in the PDE4 assay describedherein. In yet further embodiments, compounds will exhibit an IC₅₀ withrespect to PDE4 of not more than about 200 nM.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder.This amount will achieve the goal of reducing or eliminating the saiddisease or disorder.

The term “therapeutically acceptable” refers to those compounds (orsalts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitablefor use in contact with the tissues of patients without undue toxicity,irritation, and allergic response, are commensurate with a reasonablebenefit/risk ratio, and are effective for their intended use.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis. The term “patient” means all mammals includinghumans. Examples of patients include humans, cows, dogs, cats, goats,sheep, pigs, and rabbits. Preferably, the patient is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds disclosed herein may also exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the compound, or parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug. An example, without limitation, ofa prodrug would be a compound which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound.

The compounds disclosed herein can exist as therapeutically acceptablesalts. The present invention includes compounds listed above in the formof salts, including acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable. However, salts ofnon-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable. For a morecomplete discussion of the preparation and selection of salts, refer toPharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds disclosed herein can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides.Examples of acids which can be employed to form therapeuticallyacceptable addition salts include inorganic acids such as hydrochloric,hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic,maleic, succinic, and citric. Salts can also be formed by coordinationof the compounds with an alkali metal or alkaline earth ion. Hence, thepresent invention contemplates sodium, potassium, magnesium, and calciumsalts of the compounds disclosed herein, and the like.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reaction of a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

A salt of a compound can be made by reaction of the appropriatecompound, in the form of the free base, with the appropriate acid.

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical formulation. Accordingly, provided herein arepharmaceutical formulations which comprise one or more of certaincompounds disclosed herein, or one or more pharmaceutically acceptablesalts, esters, prodrugs, amides, or solvates thereof, together with oneor more pharmaceutically acceptable carriers thereof and optionally oneor more other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art; e.g., in Remington'sPharmaceutical Sciences. The pharmaceutical compositions disclosedherein may be manufactured in any manner known in the art, e.g., bymeans of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual and intraocular)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. Typically, thesemethods include the step of bringing into association a compound of thesubject invention or a pharmaceutically acceptable salt, ester, amide,prodrug or solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the compounds disclosed herein suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds disclosed herein may be administered topically, thatis by non-systemic administration. This includes the application of acompound disclosed herein externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose. The active ingredient for topical administration maycomprise, for example, from 0.001% to 10% w/w (by weight) of theformulation. In certain embodiments, the active ingredient may compriseas much as 10% w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/wof the formulation.

Topical ophthalmic, otic, and nasal formulations of the presentinvention may comprise excipients in addition to the active ingredient.Excipients commonly used in such formulations include, but are notlimited to, tonicity agents, preservatives, chelating agents, bufferingagents, and surfactants. Other excipients comprise solubilizing agents,stabilizing agents, comfort-enhancing agents, polymers, emollients,pH-adjusting agents and/or lubricants. Any of a variety of excipientsmay be used in formulations of the present invention including water,mixtures of water and water-miscible solvents, such as C1-C7-alkanols,vegetable oils or mineral oils comprising from 0.5 to 5% non-toxicwater-soluble polymers, natural products, such as alginates, pectins,tragacanth, karaya gum, guar gum, xanthan gum, carrageenin, agar andacacia, starch derivatives, such as starch acetate and hydroxypropylstarch, and also other synthetic products such as polyvinyl alcohol,polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide,preferably cross-linked polyacrylic acid and mixtures of those products.The concentration of the excipient is, typically, from 1 to 100,000times the concentration of the active ingredient. In preferredembodiments, the excipients to be included in the formulations aretypically selected on the basis of their inertness towards the activeingredient component of the formulations.

Relative to ophthalmic, otic, and nasal formulations, suitabletonicity-adjusting agents include, but are not limited to, mannitol,sodium chloride, glycerin, sorbitol and the like. Suitable bufferingagents include, but are not limited to, phosphates, borates, acetatesand the like. Suitable surfactants include, but are not limited to,ionic and nonionic surfactants (though nonionic surfactants arepreferred), RLM 100, POE 20 cetylstearyl ethers such as Procol® CS20 andpoloxamers such as Pluronic° F68.

The formulations set forth herein may comprise one or morepreservatives. Examples of such preservatives include p-hydroxybenzoicacid ester, sodium perborate, sodium chlorite, alcohols such aschlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivativessuch as polyhexamethylene biguanide, sodium perborate, polyquaternium-1,amino alcohols such as AMP-95, or sorbic acid. In certain embodiments,the formulation may be self-preserved so that no preservation agent isrequired.

For ophthalmic, otic, or nasal administration, the formulation may be asolution, a suspension, or a gel. In preferred aspects, the formulationsare for topical application to the eye, nose, or ear in aqueous solutionin the form of drops. The term “aqueous” typically denotes an aqueousformulation wherein the formulation is >50%, more preferably >75% and inparticular >90% by weight water. These drops may be delivered from asingle dose ampoule which may preferably be sterile and thus renderbacteriostatic components of the formulation unnecessary. Alternatively,the drops may be delivered from a multi-dose bottle which may preferablycomprise a device which extracts any preservative from the formulationas it is delivered, such devices being known in the art.

For ophthalmic disorders, components of the invention may be deliveredto the eye as a concentrated gel or a similar vehicle, or as dissolvableinserts that are placed beneath the eyelids.

The formulations of the present invention that are adapted for topicaladministration to the eye are preferably isotonic, or slightly hypotonicin order to combat any hypertonicity of tears caused by evaporationand/or disease. This may require a tonicity agent to bring theosmolality of the formulation to a level at or near 210-320 milliosmolesper kilogram (mOsm/kg). The formulations of the present inventiongenerally have an osmolality in the range of 220-320 mOsm/kg, andpreferably have an osmolality in the range of 235-300 mOsm/kg. Theophthalmic formulations will generally be formulated as sterile aqueoussolutions.

In certain ophthalmic embodiments, the compositions of the presentinvention are formulated with one or more tear substitutes. A variety oftear substitutes are known in the art and include, but are not limitedto: monomeric polyols, such as, glycerol, propylene glycol, and ethyleneglycol; polymeric polyols such as polyethylene glycol; cellulose esterssuch hydroxypropylmethyl cellulose, carboxy methylcellulose sodium andhydroxy propylcellulose; dextrans such as dextran 70; vinyl polymers,such as polyvinyl alcohol; and carbomers, such as carbomer 934P,carbomer 941, carbomer 940 and carbomer 974P. Certain formulations ofthe present invention may be used with contact lenses or otherophthalmic products.

In certain embodiments, formulations are prepared using a bufferingsystem that maintains the formulation at a pH of about 4.5 to a pH ofabout 8. A most preferred formulation pH is from 7 to 8.

In certain embodiments, a formulation of the present invention isadministered once a day. However, the formulations may also beformulated for administration at any frequency of administration,including once a week, once every 5 days, once every 3 days, once every2 days, twice a day, three times a day, four times a day, five times aday, six times a day, eight times a day, every hour, or any greaterfrequency. Such dosing frequency is also maintained for a varyingduration of time depending on the therapeutic regimen. The duration of aparticular therapeutic regimen may vary from one-time dosing to aregimen that extends for months or years. The formulations areadministered at varying dosages, but typical dosages are one to twodrops at each administration, or a comparable amount of a gel or otherformulation. One of ordinary skill in the art would be familiar withdetermining a therapeutic regimen for a specific indication.

Gels for topical or transdermal administration may comprise, generally,a mixture of volatile solvents, nonvolatile solvents, and water. Incertain embodiments, the volatile solvent component of the bufferedsolvent system may include lower (C1-C6) alkyl alcohols, lower alkylglycols and lower glycol polymers. In further embodiments, the volatilesolvent is ethanol. The volatile solvent component is thought to act asa penetration enhancer, while also producing a cooling effect on theskin as it evaporates. The nonvolatile solvent portion of the bufferedsolvent system is selected from lower alkylene glycols and lower glycolpolymers. In certain embodiments, propylene glycol is used. Thenonvolatile solvent slows the evaporation of the volatile solvent andreduces the vapor pressure of the buffered solvent system. The amount ofthis nonvolatile solvent component, as with the volatile solvent, isdetermined by the pharmaceutical compound or drug being used. When toolittle of the nonvolatile solvent is in the system, the pharmaceuticalcompound may crystallize due to evaporation of volatile solvent, whilean excess may result in a lack of bioavailability due to poor release ofdrug from solvent mixture. The buffer component of the buffered solventsystem may be selected from any buffer commonly used in the art; incertain embodiments, water is used. A common ratio of ingredients isabout 20% of the nonvolatile solvent, about 40% of the volatile solvent,and about 40% water. There are several optional ingredients which can beadded to the topical composition. These include, but are not limited to,chelators and gelling agents. Appropriate gelling agents can include,but are not limited to, semisynthetic cellulose derivatives (such ashydroxypropylmethylcellulose) and synthetic polymers, galactomannanpolymers (such as guar and derivatives thereof), and cosmetic agents.

Lotions include those suitable for application to the skin or eye. Aneye lotion may comprise a sterile aqueous solution optionally containinga bactericide and may be prepared by methods similar to those for thepreparation of drops. Lotions or liniments for application to the skinmay also include an agent to hasten drying and to cool the skin, such asan alcohol or acetone, and/or a moisturizer such as glycerol or an oilsuch as castor oil or arachis oil.

Creams, ointments or pastes are semi-solid formulations of the activeingredient for external application. They may be made by mixing theactive ingredient in finely-divided or powdered form, alone or insolution or suspension in an aqueous or non-aqueous fluid, with the aidof suitable machinery, with a greasy or non-greasy base. The base maycomprise hydrocarbons such as hard, soft or liquid paraffin, glycerol,beeswax, a metallic soap; a mucilage; an oil of natural origin such asalmond, corn, arachis, castor or olive oil; wool fat or its derivativesor a fatty acid such as steric or oleic acid together with an alcoholsuch as propylene glycol or a macrogel. The formulation may incorporateany suitable surface active agent such as an anionic, cationic ornon-ionic surfactant such as a sorbitan ester or a polyoxyethylenederivative thereof. Suspending agents such as natural gums, cellulosederivatives or inorganic materials such as silicaceous silicas, andother ingredients such as lanolin, may also be included.

Drops may comprise sterile aqueous or oily solutions or suspensions andmay be prepared by dissolving the active ingredient in a suitableaqueous solution of a bactericidal and/or fungicidal agent and/or anyother suitable preservative, and, in certain embodiments, including asurface active agent. The resulting solution may then be clarified byfiltration, transferred to a suitable container which is then sealed andsterilized by autoclaving or maintaining at 98-100° C. for half an hour.Alternatively, the solution may be sterilized by filtration andtransferred to the container by an aseptic technique. Examples ofbactericidal and fungicidal agents suitable for inclusion in the dropsare phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride(0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for thepreparation of an oily solution include glycerol, diluted alcohol andpropylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray. Pressurized packs maycomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form, in for example, capsules, cartridges,gelatin or blister packs from which the powder may be administered withthe aid of an inhalator or insufflator.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations described above may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Compounds may be administered orally or via injection at a dose of from0.1 to 500 mg/kg per day. The dose range for adult humans is generallyfrom 5 mg to 2 g/day. Tablets or other forms of presentation provided indiscrete units may conveniently contain an amount of one or morecompounds which is effective at such dosage or as a multiple of thesame, for instance, units containing 5 mg to 500 mg, usually around 10mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The compounds can be administered in various modes, e.g. orally,topically, or by injection. The precise amount of compound administeredto a patient will be the responsibility of the attendant physician. Thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diets, time ofadministration, route of administration, rate of excretion, drugcombination, the precise disorder being treated, and the severity of theindication or condition being treated. Also, the route of administrationmay vary depending on the condition and its severity.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein (or a pharmaceutically acceptablesalt, ester, or prodrug thereof) in combination with another therapeuticagent. By way of example only, if one of the side effects experienced bya patient upon receiving one of the compounds herein is hypertension,then it may be appropriate to administer an anti-hypertensive agent incombination with the initial therapeutic agent. Or, by way of exampleonly, the therapeutic effectiveness of one of the compounds describedherein may be enhanced by administration of an adjuvant (i.e., by itselfthe adjuvant may only have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Or, by way of example only, thebenefit of experienced by a patient may be increased by administeringone of the compounds described herein with another therapeutic agent(which also includes a therapeutic regimen) that also has therapeuticbenefit. By way of example only, in a treatment for diabetes involvingadministration of one of the compounds described herein, increasedtherapeutic benefit may result by also providing the patient withanother therapeutic agent for diabetes. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

Specific, non-limiting examples of possible combination therapiesinclude use of certain compounds of the invention with: H₁antihistaminics, such as olopatadine hydrochloride and anti-infectives,such as moxifloxacin, gatifloxacin, finafloxacin, ciprofloxacin,lomefloxacin, levofloxacin, and norfloxacin. In any case, the multipletherapeutic agents (at least one of which is a compound disclosedherein) may be administered in any order or even simultaneously. Ifsimultaneously, the multiple therapeutic agents may be provided in asingle, unified form, or in multiple forms (by way of example only,either as a single pill or as two separate pills). One of thetherapeutic agents may be given in multiple doses, or both may be givenas multiple doses. If not simultaneous, the timing between the multipledoses may be any duration of time ranging from a few minutes to fourweeks.

Thus, in another aspect, the present invention provides methods fortreating PDE4-mediated disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound of the present invention effective to reduce or prevent saiddisorder in the subject in combination with at least one additionalagent for the treatment of said disorder that is known in the art. In arelated aspect, the present invention provides therapeutic compositionscomprising at least one compound of the present invention in combinationwith one or more additional agents for the treatment of PDE4-mediateddisorders.

Compounds of the subject invention may be useful in treatingPDE4-mediated disease, disorders and conditions. In certain embodiments,said compounds may find use in treating acute and chronic pain andinflammation. The compounds of the present invention may be useful totreat patients with neuropathy, neuropathic pain, or inflammatory painsuch as reflex sympathetic dystrophy/causalgia (nerve injury),peripheral neuropathy (including diabetic neuropathy), intractablecancer pain, complex regional pain syndrome, and entrapment neuropathy(carpel tunnel syndrome). The compounds may also be useful in thetreatment of pain associated with acute herpes zoster (shingles),postherpetic neuralgia (PHN), and associated pain syndromes such asocular pain. The compounds may further be useful as analgesics in thetreatment of pain such as surgical analgesia, or as an antipyretic forthe treatment of fever. Pain indications include, but are not limitedto, post-surgical pain for various surgical procedures includingpost-cardiac surgery, dental pain/dental extraction, pain resulting fromcancer, muscular pain, mastalgia, pain resulting from dermal injuries,lower back pain, headaches of various etiologies, including migraine,and the like. The compounds may also be useful for the treatment ofpain-related disorders such as tactile allodynia and hyperalgesia. Thepain may be somatogenic (either nociceptive or neuropathic), acuteand/or chronic. The PDE4 inhibitors of the subject invention may also beuseful in conditions where NSAIDs, morphine or fentanyl opiates and/orother opioid analgesics would traditionally be administered.

Furthermore, compounds of the subject invention may be used in thetreatment or prevention of opiate tolerance in patients needingprotracted opiate analgesics, and benzodiazepine tolerance in patientstaking benzodiazepines, and other addictive behavior, for example,nicotine addiction, alcoholism, and eating disorders. Moreover, thecompounds and methods of the present invention may be useful in thetreatment or prevention of drug withdrawal symptoms, for exampletreatment or prevention of symptoms of withdrawal from opiate, alcohol,or tobacco addiction.

In addition, compounds of the subject invention may be used to treatinsulin resistance and other metabolic disorders such as atherosclerosisthat are typically associated with an exaggerated inflammatorysignaling.

The present invention encompasses therapeutic methods using novelselective PDE4 inhibitors to treat or prevent respiratory disease orconditions, including therapeutic methods of use in medicine forpreventing and treating a respiratory disease or condition including:asthmatic conditions including allergen-induced asthma, exercise-inducedasthma, pollution-induced asthma, cold-induced asthma, andviral-induced-asthma; asthma-related diseases such as airwayhyperreactivity and small airway disease; chronic obstructive pulmonarydiseases including chronic bronchitis with normal airflow, chronicbronchitis with airway obstruction (chronic obstructive bronchitis),emphysema, asthmatic bronchitis, and bullous disease; and otherpulmonary diseases involving inflammation including bronchiolitis,bronchioectasis, cystic fibrosis, pigeon fancier's disease, farmer'slung, acute respiratory distress syndrome, pneumonia, pneumonitis,aspiration or inhalation injury, fat embolism in the lung, acidosisinflammation of the lung, acute pulmonary edema, acute mountainsickness, acute pulmonary hypertension, persistent pulmonaryhypertension of the newborn, perinatal aspiration syndrome, hyalinemembrane disease, acute pulmonary thromboembolism, heparin-protaminereactions, sepsis, status asthamticus, hypoxia, dyspnea, hypercapnea,hyperinflation, hypoxemia, and cough. Further, compounds disclosedherein would find use in the treatment of allergic disorders such asdelayed type hypersensitivity reaction, allergic contact dermatitis,allergic rhinitis, and chronic sinusitis.

Other disorders or conditions which may be treated by the compounds ofthe present invention include inflammation and related disorders. Thecompounds of the present invention may be useful as anti-inflammatoryagents with the additional benefit of having significantly less harmfulside effects. The compounds may be useful to treat arthritis, includingbut not limited to rheumatoid arthritis, spondyloarthropathies, goutyarthritis, osteoarthritis, juvenile arthritis, acute rheumaticarthritis, enteropathic arthritis, neuropathic arthritis, psoriaticarthritis, reactive arthritis (Reiter's syndrome), and pyogenicarthritis, and autoimmune diseases, including systemic lupuserythematosus, hemolytic syndromes, autoimmune hepatitis, autoimmuneneuropathy, vitiglio (autoimmune thyroiditis), Hashimoto's thyroiditis,anemias, myositis including polymyositis, alopecia greata, Goodpasture'ssyndrome, hypophytis, and pulmonary fibrosis.

The compounds may also be useful in treating osteoporosis and otherrelated bone disorders.

These compounds may also be used to treat gastrointestinal conditionssuch as reflux esophagitis, diarrhea, inflammatory bowel disease,Crohn's disease, gastritis, irritable bowel syndrome, Graves' disease(hyperthyroidism), necrotizing enterocolitis, and ulcerative colitis.The compounds may also be used in the treatment of pulmonaryinflammation, such as that associated with viral infections and cysticfibrosis.

In addition, compounds of invention may also be useful in organtransplant patients either alone or in combination with conventionalimmunomodulators. Examples of conditions to be treated in said patientsinclude graft vs. host reaction (i.e., graft vs. host disease),allograft rejections (e.g., acute allograft rejection, and chronicallograft rejection), transplant reperfusion injury, and earlytransplantation rejection (e.g., acute allograft rejection).

Yet further, the compounds of the invention may be useful in thetreatment of pruritis and vitaligo.

The compounds of the present invention may also be useful in treatingtissue damage in such diseases as vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, neuromuscular junctiondisease including myasthenia gravis, white matter disease includingmultiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome,Langerhans' cell histiocytosis, glomerulonephritis, reperfusion injury,pancreatitis, interstitial cystitis, Behcet's syndrome, polymyositis,gingivitis, periodontis, hypersensitivity, swelling occurring afterinjury, ischemias including myocardial ischemia, cardiovascularischemia, and ischemia secondary to cardiac arrest, cirrhosis, septicshock, endotoxic shock, gram negative sepsis, toxic shock syndrome,stroke, ischemia reperfusion injury, multi-organ dysfunction, restenosisincluding restenosis following coronary bypass surgery, and the like.

The compounds of the subject invention may also be useful for thetreatment of certain diseases and disorders of the nervous system.Central nervous system disorders in which PDE4 inhibition may be usefulinclude cortical dementias including Alzheimer's disease and mildcognitive impairment (MCI), central nervous system damage resulting fromstroke, ischemias including cerebral ischemia (both focal ischemia,thrombotic stroke and global ischemia (for example, secondary to cardiacarrest), and trauma. Neurodegenerative disorders in which PDE4inhibition may be useful include nerve degeneration or nerve necrosis indisorders such as hypoxia, hypoglycemia, epilepsy, and in cases ofcentral nervous system (CNS) trauma (such as spinal cord and headinjury), hyperbaric oxygen convulsions and toxicity, dementia e.g.pre-senile dementia, and AIDS-related dementia, cachexia, Sydenham'schorea, Huntington's disease, Parkinson's Disease, amyotrophic lateralsclerosis (ALS), Korsakoff s syndrome, and imbecility relating to acerebral vessel disorder. Further disorders in which PDE4 inhibitionmight prove useful include neuropathies of the central and peripheralnervous system (including, for example, IgA neuropathy, membranousneuropathy and idiopathic neuropathy), chronic inflammatorydemyelinating polyneuropathy, transverse myelitis, Gullain-Barredisease, encephalitis, and cancers of the nervous system. Disorders ofCNS function in which PDE4 inhibitors may find use include sleepingdisorders, schizophrenia, depression, depression or other symptomsassociated with Premenstrual Syndrome (PMS), and anxiety.

Furthermore, the compounds of the present invention may also be usefulin inhibiting PDE4 activity for the amelioration of systemic disordersincluding systemic hypotension associated with septic and/or toxichemorrhagic shock induced by a wide variety of agents; as a therapy withcytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short termimmunosuppression in transplant therapy.

Still other disorders or conditions which may be treated by thecompounds of the subject invention include the prevention or treatmentof cancer, such as colorectal cancer, and cancer of the breast, lung,prostate, bladder, cervix and skin. Compounds of the invention may beused in the treatment and prevention of neoplasias including but notlimited to brain cancer, bone cancer, leukemia, lymphoma, epithelialcell-derived neoplasia (epithelial carcinoma) such as basal cellcarcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer,mouth cancer, esophageal cancer, small bowel cancer and stomach cancer,colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarycancer, cervical cancer, lung cancer, breast cancer and skin cancer,such as squamous cell and basal cell cancers, prostate cancer, renalcell carcinoma, and other known cancers that effect epithelial cellsthroughout the body. The neoplasia can be selected from gastrointestinalcancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer,prostate cancer, cervical cancer, lung cancer, breast cancer and skincancer, such as squamous cell and basal cell cancers. The presentcompounds and methods may also be used to treat the fibrosis whichoccurs with radiation therapy. The present compounds and methods may beused to treat subjects having adenomatous polyps, including those withfamilial adenomatous polyposis (FAP). Additionally, the presentcompounds and methods may be used to prevent polyps from forming inpatients at risk of FAP.

The compounds disclosed herein can be used in the treatment of oticdiseases and otic allergic disorders, including eustachian tube itching.

The compounds of the subject invention may be used in the treatment ofophthalmic diseases, such as ophthalmic allergic disorders, includingallergic conjunctivitis, vernal conjunctivitis, vernalkeratoconjunctivitis, and giant papillary conjunctivitis, dry eye,glaucoma, corneal neovascularization, optic neuritis, Sjogren'ssyndrome, retinal ganglion degeneration, ocular ischemia, retinitis,retinopathies, uveitis, ocular photophobia, and of inflammation and painassociated with acute injury to the eye tissue. Specifically, thecompounds may be used to treat glaucomatous retinopathy and/or diabeticretinopathy. The compounds may also be used to treat post-operativeinflammation or pain as from ophthalmic surgery such as cataract surgeryand refractive surgery. In certain embodiments, the compounds of thepresent invention are used to treat an allergic eye disease selectedfrom the group consisting of allergic conjunctivitis; vernalconjunctivitis; vernal keratoconjunctivitis; and giant papillaryconjunctivitis.

Moreover, compounds of the subject invention may be used in thetreatment of menstrual cramps, dysmenorrhea, premature labor,endometriosis, tendonitis, bursitis, skin-related conditions such aspsoriasis, eczema, burns, sunburn, dermatitis, pancreatitis, hepatitis,lichen planus, scleritis, scleroderma, dermatomyositis, and the like.Other conditions in which the compounds of the subject invention may beused include diabetes (type I or type II), atherosclerosis, congestiveheart failure, myocarditis, atherosclerosis, cerebral ischemia,angiogenesis, pulmonary hypertension, and aortic aneurysm.

The present compounds may also be used in co-therapies, partially orcompletely, in place of other conventional anti-inflammatory therapies,such as together with steroids, NSAIDs, COX-2 selective inhibitors,5-lipoxygenase inhibitors, LTB₄ antagonists and LTA₄ hydrolaseinhibitors. The compounds of the subject invention may also be used toprevent tissue damage when therapeutically combined with antibacterialor antiviral agents.

Besides being useful for human treatment, certain compounds andformulations disclosed herein may also be useful for veterinarytreatment of companion animals, exotic animals and farm animals,including mammals, rodents, and the like. More preferred animals includehorses, dogs, and cats.

All references, patents or applications, U.S. or foreign, cited in theapplication are hereby incorporated by reference as if written herein intheir entireties. Where any inconsistencies arise, material literallydisclosed herein controls.

GENERAL SYNTHETIC METHODS FOR PREPARING COMPOUNDS

The following schemes can be used to practice the present invention.

The invention is further illustrated by the following examples.

EXAMPLE 18-(Cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

Step 1

Sulfuric acid (3.0 mL, 56 mmol) was added dropwise over 2 min to asolution of methyl 3-hydroxy-4-methoxybenzoate (3.64 g, 20 mmol),tetrabutylammonium hydrogensulfate (340 mg, 1.0 mmol), isopropyl nitrate(5.0 mL, 50 mmol), and dichloromethane (CH₂Cl₂) (40 mL) at 0° C. Thereaction was allowed to warm to room temperature, maintained for 45 min,and then quenched with ice water (100 mL). This mixture was extractedwith dichloromethane (250 mL×2). The combined extracts were dried,filtered, concentrated, and purified by silica gel chromatography(4:1→3:7; hexanes:ethyl acetate) to give methyl3-hydroxy-4-methoxy-2-nitrobenzoate: MS (ESI): 228.4.

Step 2

A mixture of methyl 3-hydroxy-4-methoxy-2-nitrobenzoate (1.14 g, 5.0mmol), bromocyclopentane (0.7 mL, 6.5 mmol), potassium carbonate (2.0 g,14 mmol), and anhydrous acetonitrile (15 mL) was refluxed under N₂.After 19 h, the reaction was allowed to cool to room temperature,concentrated, and purified by silica gel chromatography (4:1→3:2;hexanes:ethyl acetate) to give methyl3-(cyclopentyloxy)-4-methoxy-2-nitrobenzoate: MS (ESI): 296.5.

Step 3

A mixture of methyl 3-(cyclopentyloxy)-4-methoxy-2-nitrobenzoate (750mg, 2.54 mmol), 10% Pd/C (50% H₂O, 500 mg, 0.23 mmol Pd), and methanol(10 mL) was stirred vigorously at 23° C. under an atmosphere of H₂.After 21 h, the mixture was filtered through Celite and concentrated togive methyl 2-amino-3-(cyclopentyloxy)-4-methoxybenzoate: MS (ESI):266.5.

Step 4

A solution of methyl 2-amino-3-(cyclopentyloxy)-4-methoxybenzoate (5.54g, 20.9 mmol), acetic anhydride (21.0 mL, 222 mmol), and dioxane (35 mL)was heated at 40° C. under N₂ for 17 h and then allowed to cool to roomtemperature. Water (10 mL) was added, and after 15 min of stirring, thereaction was concentrated to give methyl2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate: MS (ESI): 307.9.

Step 5

A solution of methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate(6.42 g, 20.9 mmol) and anhydrous tetrahydrofuran (THF) (60 mL) wasadded via syringe pump (1 mL/min) to a solution of potassiumbis(trimethylsilyl)amide (KHMDS) (150 mL, 0.5M PhMe, 75 mmol) at −78° C.under N₂. The reaction was allowed to slowly warm to room temperature asthe bath expired overnight. After 17 h, the reaction was poured intoice/water (250 mL), let stir for 10 min, and the layers were separated.The aqueous was washed with ether (150 mL), acidified with conc. HCl (7mL), and filtered to give8-(cyclopentyloxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one: MS (ESI):276.0.

Step 6

A mixture of 8-(cyclopentyloxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one(350 mg, 1.3 mmol), ammonium acetate (4.0 g, 52 mmol), and anhydrousm-xylene (10 mL) was heated at 150° C. under N₂ for 48 h and thenallowed to cool to room temperature. The mixture was concentrated todryness, diluted with water (25 mL), stirred for 2 min, sonicated for 1min, and then stirred for 5 min. The free-flowing solid was filtered,washed with water (25 mL), and pumped to dryness to give4-amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one: MS (ESI): 274.9.

Step 7

4-Amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one (340 mg, 1.24mmol) was added in 3 portions over 5 minutes to a mixture of sodiumhydride (NaH) (110 mg, 60%, 2.75 mmol) and DMSO (4 mL) at roomtemperature under N₂. After 5 min, 3,4,5-trichloropyridine (271 mg, 1.49mmol) was added. After 19 h, more sodium hydride (100 mg, 60%, 2.5 mmol)was added followed by more 3,4,5-trichloropyridine (250 mg, 1.37 mmol).After an additional 4 h, the reaction was poured into 1M KH₂PO₄ (75 mL)and stirred for 5 min. The solids were filtered, washed with water (25mL), and then purified by reverse-phase HPLC (3:7→1:0;acetonitrile:water). In some cases, additional purification by silicagel chromatography (1:0→0:1; dichlormethane:methanol) was needed to give8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.86 (s, 1H), 8.76 (s, 2H),7.87 (d, 1H), 7.06 (d, 1), 4.97 (m, 1H), 4.78 (s, 1H), 3.90 (s, 3H),1.83-1.48 (m, 8H); MS (ESI): 419.7.

EXAMPLE 28-(Cyclopentyloxy)-4-(3,5-dichloropyridin-4-yloxy)-7-methoxyquinolin-2(1H)-one

The title compound was isolated from the purification of Example 1, Step7. ¹H NMR (400 MHz, DMSO-d₆): δ 10.28 (s, 1H), 8.84 (s, 2H), 7.71 (d,1H), 7.11 (d, 1H), 5.35 (s, 1H), 4.97 (m, 1H), 3.91 (s, 3H), 1.86-1.43(m, 8H); MS (ESI): 420.7.

EXAMPLE 38-(Cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from methyl3-hydroxy-4-methoxy-2-nitrobenzoate (Example 1, Step 1) and(bromomethyl)cyclopropane following the procedures outlined inExample 1. ¹H NMR (400 MHz, DMSO-d₆): δ 9.91 (s, 1H), 8.83 (s, 1H), 8.76(s, 2H), 7.87 (d, 1H), 7.03 (d, 1H), 4.78 (s, 1H), 3.89 (s, 3H), 3.84(d, 2H), 1.27 (m, 1H), 0.45 (m, 2H), 0.25 (m, 2H); MS (ESI): 405.8.

EXAMPLE 48-(Cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-1-methylquinolin-2(1H)-one

Step 1

A solution of methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate(1.6 g, 5.2 mmol, Example 1, Step 4) and anhydrous tetrahydrofuran (30mL) was added over 5 min to a mixture of sodium hydride (230 mg, 5.75mmol) and anhydrous tetrahydrofuran (10 mL) at 0° C. under N₂. Thereaction was allowed to warm to room temperature and after 20 min,cooled back to 0° C. A solution of iodomethane (1.06 g, 0.0075 mol) andanhydrous tetrahydrofuran (10 mL) was added over 3 min. The reaction wasallowed to warm to room temperature and after 30 min, concentrated. Theresidue was diluted with ethyl acetate (40 mL) and washed with brine (10mL×2). The organic layer was dried, filtered, and concentrated to givemethyl 3-(cyclopentyloxy)-4-methoxy -2-(N-methylacetamido)benzoate: MS(ESI): 322.1.

Step 2

The title compound was prepared from methyl3-(cyclopentyloxy)-4-methoxy-2-(N-methylacetamido)benzoate following theprocedures outlined in Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s,1H), 8.74 (s, 2H), 7.92 (d, 1H), 7.13 (d, 1H), 4.92 (s, 1H), 4.53 (m,1H), 3.90 (s, 3H), 3.59 (s, 3H), 1.80-1.48 (m, 8H); MS (ESI): 433.9.

EXAMPLE 58-(Cyclopentyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from 4-bromo-3,5-dimethylpyridine and4-amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one (Example 1, Step6) following the procedure outlined in Example 8. ¹H NMR (400 MHz,DMSO-d₆): δ 9.08 (s, 1H), 8.44 (s, 1H), 8.40 (s, 2H), 7.88 (d, 1H), 7.03(d, 1H), 4.96 (m, 1H), 4.51 (s, 1H), 3.90 (s, 3H), 2.13 (s, 6H),1.80-1.54 (m, 8H); MS (ESI): 380.2.

EXAMPLE 61,3-Dibromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

N-Bromosuccinimide (0.118 g, 0.61 mmol) was added to a solution of4-(3,5-dichloropyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one(0.100 g, 0.240 mmol, Example 1) and anhydrous dimethylformamide (2 mL)at 0° C. After 2 h at 0° C., the mixture was poured into water, and theprecipitate was filtered to give1,3-dibromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 10.5 (s, 1H), 8.59 (s, 2H), 6.76 (d, 1H),6.61 (d, 1H), 4.87 (m, 1H), 3.80 (s, 3H), 1.82-1.51 (m, 8H); MS (ESI):575.8.

EXAMPLE 73-Bromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

N-Bromosuccinimide (0.104 g, 0.585 mmol) was added to a solution of4-(3,5-dichloropyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one(0.246 g, 0.585 mmol, Example 1) and anhydrous dimethylformamide (3 mL)at 0° C. After 4 h at 0° C., the mixture was poured into water, and theprecipitate was filtered. Saturated sodium thiosulfate solution (1 mL)was added to a solution of the filter cake and methanol (5 mL). Afterthe dibromo intermediate was consumed, as monitored by LCMS, the mixturewas diluted with water and extracted with ethyl acetate. The organicextract was dried, filtered, and concentrated to give3-bromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 8.88 (br s, 1H), 8.42 (s,2H), 7.62 (d, 1H), 7.04 (d, 1H), 4.98 (m, 1H), 3.89 (s, 3H), 1.84-1.51(m, 8H); MS (ESI): 497.8.

EXAMPLE 88-(Cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

A solution of 4-bromo-3,5-dimethylpyridine (1.16 g, 6.21 mmol) anddegassed toluene (5 mL) was added to a mixture of4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one (1.94 g, 7.45mmol, intermediate for Example 3),tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃), (0.28 g, 0.31mmol), 2,2-dicyclohexylphosphorane triisopropylbiphenyl (0.59 g, 1.24mmol), sodium tert-butoxide (1.20 g, 12.4 mmol), and degassed toluene(20 mL) under N₂. The mixture was heated at 110° C. for 2 h, allowed tocool to room temperature, sonicated until the solids broke up, and thenfiltered through Celite with ethyl acetate (500 mL). The filtrate wasconcentrated, purified by silica gel chromatography (0→8%methanol/dichloromethane), and then re-purified by reverse-phase HPLC(25→100% acetonitrile/H₂O) to give8-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 9.64 (s, 1H), 8.43 (s, 1H), 8.42 (s, 2H),7.89 (d, 1H), 7.03 (d, 1H), 4.54 (s, 1H), 3.91 (s, 3H), 3.85 (d, 2H),2.15 (s, 6H), 1.28 (m, 1H), 0.47 (m, 2H), 0.28 (m, 2H); MS (ESI): 365.8.

EXAMPLE 98-(Cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-hydroxyethyl)-7-methoxyquinolin-2(1H)-one

Step 1

Methyl3-(cyclopentyloxy)-4-methoxy-2-(N-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido)benzoatewas prepared from methyl2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate (Example 1, Step 4) and2-(2-bromoethoxy)-tetrahydro-2H-pyran following the procedure outlinedin Example 4 (with the following exceptions: the solvent used wasdimethylformamide, the reaction temperature was 33° C., and the reactionwas conducted overnight). MS (ESI): 458.2 (M+Na).

Step 2

8-(Cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)quinolin-2(1H)-onewas prepared from methyl3-(cyclopentyloxy)-4-methoxy-2-(N-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido)benzoatefollowing the procedures outlined in Example 1. MS (ESI): 570 (M+Na).

Step 3

para-Toluenesulfonic acid (172 mg, 1.0 mmol) was added to a solution of8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)quinolin-2(1H)-one(2.4 g, 4.4 mmol) and methanol (100 mL). After stirring overnight, thereaction was concentrated, diluted with dichloromethane (100 mL), andthen washed with saturated NaHCO₃ (20 mL) followed by water (20 mL). Theorganic layer was dried, filtered, concentrated, and recrystallized fromdichloromethane/petroleum ether (1:2) to give8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-hydroxyethyl)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 8.74 (s, 2H), 8.73 (s, 1H), 7.91 (d, 1H),7.11 (d, 1H), 4.92 (s, 1H), 4.65 (t, 2H), 4.59 (m, 1H), 4.50 (t, 1H),3.90 (s, 3H), 3.32 (m 2H), 1.80-1.48 (m, 8H); MS (ESI): 463.9.

EXAMPLE 108-(Cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-(dimethylamino)ethyl)-7-methoxyquinolin-2(1H)-one

Step 1

Dess-Martin periodinane (933 mg, 2.2 mmol) was added to a solution of8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-hydroxyethyl)-7-methoxyquinolin-2(1H)-one(500 mg, 1.08 mmol, Example 9) and CH₂Cl₂ (30 mL) at 0° C. After 30 min,the mixture was allowed to warm to room temperature. When the startingmaterial was consumed, the reaction was diluted with dichloromethane (25mL), washed with aq. NaOH (20 mL×2), and then washed with water (20 mL).The organic layer was dried, filtered, concentrated, and purified bysilica gel chromatography (1:2→1:1; ethyl acetate:petroleum ether) togive2-(8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde:MS (ESI): 462.2.

Step 2

Titanium (IV) isopropoxide (496 mg, 1.74mmol) and2-(8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde(400 mg, 0.87 mmol) were added sequentially to a solution ofdimethylamine hydrochloride (144 mg, 1.74 mmol), triethylamine (176 mg,1.74 mmol), and absolute ethanol (20 mL). After stirring overnight,sodium borohydride (50 mg, 1.3 mmol) was added. After an additional 3 h,the reaction was poured into aq. ammonia (30 mL) and thenfiltered—washing with dichloromethane. The filtrate was extracted withdichloromethane (50 mL×3). The combined extracts were dried, filtered,concentrated, and purified by reverse-phase HPLC to give8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-(dimethylamino)ethyl)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s, 1H), 8.73 (s, 2H), 7.91 (d, 1H),7.12 (d, 1H), 4.94 (s, 1H), 4.71 (t, 2H), 4.58 (m, 1H), 3.90 (s, 3H),2.22 (m, 2H), 2.04 (s, 6H), 1.80-1.50 (m, 8H); MS (ESI): 491.0.

EXAMPLE 116-(4-(3,5-Dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoicacid

Step 1

Concentrated HCl (15 ml) was added to a solution of8-(cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(1.2 g, 2.90 mmol, Example 3) and methanol (8 ml). The reaction mixturewas heated at 50° C. for 4 h and then concentrated. The residue wasneutralized with saturated NaHCO₃, filtered (washed with ethanol andether), and dried to give4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one:MS (ESI): 352.

Step 2

Sodium hydride (54 mg, 1.35 mmol) was added to a solution of4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one(380 mg, 1.08 mmol) and DMSO (20 ml) room temperature under N₂. After 1h, ethyl 6-bromohexanoate (770 mg, 3.45 mmol) was added, and the mixturewas heated at 30° C. for 5 h. The reaction was quenched with drops ofwater, poured into 0.5 M KH₂PO₄, and extracted with ethyl acetate (100mL×3). The combined extracts were washed with water and then brine,dried, filtered, concentrated, and purified by silica gel chromatography(ethyl acetate: pet. ether) to give ethyl6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoate:MS (ESI): 494.0.

Step 3

Lithium hydroxide (2.0 mL, 1M, 2.0 mmol) was added to a solution ofethyl6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoate(100 mg, 0.20 mmol), methanol (2 mL), and tetrahydrofuran (8 mL). Themixture was stirred for 24 h, quenched with 1N HCl (30 mL), andextracted with ethyl acetate (40 mL×2). The organic extracts were dried,filtered, and concentrated to give6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoicacid: ¹H NMR (400 MHz, DMSO-d₆): δ 10.10 (s, 1H), 8.88 (s, 1H), 8.77 (s,2H), 7.89 (d, 1H), 7.06 (d, 1H), 4.80 (s, 1H), 3.95 (t, 2H), 3.90 (s,3H), 2.22 (t, 2H), 1.76 (m, 2H), 1.55 (m, 2H), 1.39 (m, 2H); MS (ESI):465.8.

EXAMPLE 124-(3,5-Dimethylpyridin-4-ylamino)-8-isobutoxy-7-methoxyquinolin-2(1H)-one

The title compound was prepared from methyl3-hydroxy-4-methoxy-2-nitrobenzoate (Example 1, Step 1) and1-bromo-2-methylpropane following the procedures outlined in Examples 1& 8. ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.42 (s, 1H), 8.39 (s,2H), 7.89 (d, 1H), 7.03 (d, 1H), 4.51 (s, 1H), 3.89 (s, 3H), 3.74 (d,2H), 2.13 (s, 6H), 2.13 (m, 1H), 0.97 (d, 6H); MS (ESI): 368.2.

EXAMPLE 134-(3,5-Dichloropyridin-4-ylamino)-8-(4-(dimethylamino)butoxy)-7-methoxyquinolin-2(1H)-one

Step 1

8-(4-Bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-onewas prepared from4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one(Example 11, Step 1) and 1,4-dibromobutane following the procedureoutlined in Example 11, Step 2. MS (ESI): 485.8.

Step2

A solution of dimethylamine (1.5 mL, 2M tetrahydrofuran, 3 mmol) wasadded to a solution of8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(146 mg, 0.3 mmol) and DMSO (3 mL). After 2.5 h, the reaction was pouredinto 10% K₂CO₃ (30 mL) and extracted with dichloromethane (40 mL×2). Thecombined extracts were dried, filtered, concentrated, and purified bysilical gel chromatography (1:0→4:1; dichloromethane:methanol w/1% conc.NH₄OH solution) and then reverse-phase HPLC (1:9→1:1;acetonitrile:water) to give443,5-dichloropyridin-4-ylamino)-8-(4-(dimethylamino)butoxy)-7-methoxyquinolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆): δ 10.29 (s, 1H), 8.81 (s, 1H), 8.75 (s, 2H),7.87 (d, 1H), 7.04 (d, 1H), 4.77 (s, 1H), 3.99 (t, 2H), 3.90 (s, 3H),2.27 (t, 2H), 2.13 (s, 6H), 1.73 (m, 2H), 1.54 (m, 2H); MS (ESI): 451.0.

EXAMPLE 144-(3,5-Dichloropyridin-4-ylamino)-8-(5-(dimethylamino)pentyloxy)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one(Example 11, Step 1), 1,5-dibromopentane, and dimethylamine followingthe procedures outlined in Example 13. ¹H NMR (400 MHz, DMSO-d₆): δ 9.91(s, 1H), 8.83 (s, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.77(s, 1H), 3.96 (t, 2H), 3.90 (s, 3H), 2.19 (t, 2H), 2.10 (s, 6H), 1.76(m, 2H), 1.48-1.32 (m, 4H) MS (ESI): 465.0.

Intermediate 1 Methyl 3-hydroxy-4-methoxy-2-nitrobenzoate

Nitric acid (95%, 42 g, 0.62 mol) was added dropwise (internaltemperature kept below 5° C.) to a solution of methyl3-hydroxy-4-methoxybenzoate (96.5%, 100 g, 0.53 mol) and acetic acid(250 mL) at 0° C. After 10 min at 0° C., a large amount of precipitatehad formed and was collected by filtration. The filter cake was washedwith water (100 mL×2), and then the crude product was recrystallizedfrom methanol (40 mL) to give 33 g of methyl3-hydroxy-4-methoxy-2-nitrobenzoate as a light yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 10.64 (s, 1H), 7.49 (d, 1H), 7.22 (d, 1H), 3.93 (s,3H), 3.76 (s, 3H); MS (ESI): 227.9.

Intermediate 24-Amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one

Step 1

(Bromomethyl)cyclopropane (136 g, 1.01 mol) and potassium carbonate (173g, 1.25 mol) were added to a solution of methyl3-hydroxy-4-methoxy-2-nitrobenzoate (190 g, 837 mmol) anddimethylformamide (1 L). The mixture was stirred at room temperatureovernight and then quenched with water/ice (3 L). The resulting solidswere collected by filtration, washed with water (500 mL×3), and thendried in an oven to give 220 g of methyl3-(cyclopropylmethoxy)-4-methoxy-2-nitrobenzoate as a yellow solid. MS(ESI): 281.9.

Step 2

A mixture of methyl 3-(cyclopropylmethoxy)-4-methoxy-2-nitrobenzoate(128 g, 0.46 mol), 10% Pd/C (110 g, 103 mmol Pd), and methanol (1 L) wasstirred overnight at room temperature under an atmosphere of H₂. Theresulting mixture was filtered and concentrated to give 110 g of methyl2-amino-3-(cyclopropylmethoxy)-4-methoxybenzoate as a white solid. MS(ESI): 252.1.

Step 3

Sulfuric acid (1 mL) was added dropwise to a solution of methyl2-amino-3-(cyclopropylmethoxy)-4-methoxybenzoate (98%, 187 g, 0.73 mol)and acetic anhydride (372 g, 3.65 mol). The reaction was warmed at 30°C. overnight, quenched with water/ice (1.5 L), and then stirredvigorously for 30 min. The resulting solids were collected by filtrationand dried in an oven to give 140 g of methyl2-acetamido-3-(cyclopropylmethoxy)-4-methoxybenzoate as a white solid.MS (ESI): 293.9.

Step 4

A solution of methyl2-acetamido-3-(cyclopropylmethoxy)-4-methoxybenzoate (93%, 55 g, 175mmol) and tetrahydrofuran (500 mL) was added dropwise (internaltemperature kept below −65° C.) to a solution of sodiumbis(trimethylsilyl)amide (NaHMDS) (691 mL, 1M toluene, 691 mmol) at −78°C. under N₂. The cooling bath was removed, and the reaction was stirredovernight. The reaction was quenched with water/ice (1 L) and washedwith diethyl ether (300 mL×2). The aqueous phase was adjusted to pH=3with 6 N HCl. The resulting solids were collected by filtration, washedwith water (500 mL×2), and dried in an oven to give 38.8 g of8-(cyclopropylmethoxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one as a yellowsolid. MS (ESI): 262.0.

Step 5

Ammonium acetate (620 g, 8.0 mol) was added to a solution of8-(cyclopropylmethoxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one (105 g,0.40 mol), acetic acid (400 mL), and toluene (200 mL). The reaction wasrefluxed with a Dean-Stark apparatus for 2 h, and then the mixture wasconcentrated to remove the toluene. The reaction was then refluxedovernight. Water/ice (200 mL) was added, and with external cooling, thepH was adjusted to 14 using 40% KOH. The resulting solids were collectedby filtration and then purified by silica gel chromatography(100:1→30:1; dichloromethane/methanol) to give 75 g of4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one as a lightyellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.20 (s, 1H), 7.59 (d, 1H),6.88 (d, 1H), 6.53 (s, 2H), 5.29 (s, 1H), 3.86 (s, 3H), 3.81 (d, 2H),1.22 (m, 1H), 0.44 (m, 2H), 0.22 (m, 2H); MS (ESI): 261.1.

Intermediate 34-(3,5-Dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one

Step 1

Sodium hydride (60%, 14 g, 350 mmol) was added (caution: H₂ gasevolution) to a solution of4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one (18 g, 69mmol) and DMSO (200 mL) under N₂. After 1 h at room temperature,3,4,5-trichloropyridine (12.6 g, 69 mmol) was added portionwise withexternal cooling (internal temperature kept below 30° C.), and thereaction was warmed at 32° C. overnight. The reaction was quenched withwater (40 mL) and adjusted to pH=6 with saturated potassium phosphate(KH₂PO₄). The resulting solids were collected by filtration, purified bysilica gel chromatography (100:1; dichloromethane/methanol), and thentriturated with ethyl acetate (300 mL) to give 22 g of8-(cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-quinolin-2(1H)-oneas a straw yellow solid. MS (ESI): 406.1.

Step 2

A solution of8-(cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(99%. 23.8 g, 57.9 mmol) and conc. HCl (150 mL) was warmed at 40° C. for30 min and then water (0° C., 150 mL) was added. The resulting mixturewas stirred vigorously at 0° C. for 1 h, filtered, and then washed withwater (0° C., 100 mL). A mixture of the resulting solid and 0.5 M pH 7phosphate buffer (300 mL) was stirred vigorously at 0° C. for 30 min,filtered, washed with water (0° C., 300 mL), and then dried in an ovento give 19.9 g of4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-oneas a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.69 (s, 1H), 9.51 (s,1H), 8.78 (s, 3H), 7.65 (d, 1H), 7.01 (d, 1H), 3.90 (s, 3H); MS (ESI):352.2.

Intermediate 48-(6-Chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

A mixture of4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one(Intermediate 3) (19.9 g, 56.5 mmol), cesium carbonate (36.9 g, 113mmol), and DMSO (190 mL) was heated at 30° C. for 15 minutes, and then1-bromo-6-chlorohexane (12.4 g, 62.2 mmol) was added. The reaction washeated at 30° C. for 4.5 h, diluted with ethyl acetate (2 L), washedwith 1M pH 7 phosphate buffer (2 L), and then washed with water (2L×2).The organic layer was dried, filtered, concentrated, and then purifiedby silica gel chromatography (100% ethyl acetate) to give 19 g of8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-oneas a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.01 (s, 1H), 8.87 (s,1H), 8.79 (s, 2H), 7.90 (d, 1H), 7.06 (d, 1H), 4.80 (s, 1H), 3.98 (t,2H), 3.92 (s, 3H), 3.65 (t, 2H), 1.77 (m, 4H), 1.43 (m, 4H); MS (ESI):470.3.

EXAMPLE 154-(3,5-Dichloropyridin-4-ylamino)-7-methoxy-8-(6-(4-methylpiperazin-1-yl)hexyloxy)quinolin-2(1H)-one

1-Methylpiperazine (25.5 g, 254 mmol) was added to a solution ofIntermediate 4 (10 g, 21 mmol) and DMSO (150 mL), and the solution waswarmed to 30° C. After 48 h, the solution was diluted with water (500mL) and extracted with ethyl acetate (500 mL×5). The combined extractswere dried, filtered, concentrated and then purified by silica gelchromatography (50:1; dichloromethane/methanol). Recrystallization ofthe product (7.9 g) with 10:1 methyl tent-butyl ether/dichloromethane(200 mL) gave 6.9 g of4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(6-(4-methylpiperazin-1-yl)hexyloxy)quinolin-2(1H)-oneas a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.94 (s, 1H), 8.83 (br,1H), 8.77 (s, 2H), 7.88 (d, 1H), 7.03 (d, 1H), 4.78 (s, 1H), 3.98 (t,2H), 3.79 (s, 3H), 2.28 (br, 8H), 2.21 (t, 2H), 2.11 (s, 3H), 1.74 (m,2H), 1.39 (m, 4H), 1.28 (m, 2H); MS (ESI): 534.3.

EXAMPLE4-(3,5-Dichloropyridin-4-ylamino)-7-methoxy-8-(6-morpholinohexyloxy)quinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 4) and morpholine following the procedure outlined inExample 15. ¹H NMR (400 MHz, DMSO-d₆): δ 9.97 (s, 1H), 8.83 (s, 1H),8.77 (s, 2H), 7.88 (d, 1H), 7.04 (d, 1H), 4.79 (s, 1H), 3.97 (t, 2H),3.79 (s, 3H), 3.52 (app t, 4H), 2.29 (br, 4H), 2.22 (t, 2H), 1.74 (m,2H), 1.39 (m, 4H), 1.30 (m, 2H); MS (ESI): 521.3.

EXAMPLE 174-(3,5-Dichloropyridin-4-ylamino)-8-(6-(dimethylamino)hexyloxy)-7-methoxyquinolin-2(1H)-one

Step 1

8-(6-Bromohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-onewas prepared from4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one(Intermediate 3) and 1,6-dibromohexane following the procedure outlinedfor Intermediate 4 (modifications: 1.3 equiv NaH and 2.5 equiv ofdibromide used; reaction run at room temperature). MS (ESI): 514.0.

Step 2

8-(6-Bromohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(129 mg, 0.25 mmol) was added to a solution of dimethylamine (2.0 mL, 2Mtetrahydrofuran, 4 mmol) and DMSO (0.5 mL) at room temperature. After2.5 h, the reaction was concentrated to remove the excess amine andtetrahydrofuran. The resulting solution was purified by reverse-phaseHPLC to give4-(3,5-dichloropyridin-4-ylamino)-8-(6-(dimethylamino)hexyloxy)-7-methoxyquinolin-2(1H)-one.¹H NMR (400 MHz, DMSO-d₆, HCl salt): δ 10.32 (s, 1H), 10.27 (br, 1H),9.14 (s, 1H), 8.78 (s, 2H), 7.97 (d, 1H), 7.12 (d, 1H), 4.90 (s, 1H),3.99 (t, 2H), 3.92 (s, 3H), 2.99 (m, 2H), 2.70 (d, 6H), 1.77 (m, 2H),1.65 (m, 2H), 1.43 (m, 2H), 1.33 (m, 2H); MS(ESI): 479.0.

EXAMPLE 184-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-2(1H)-one

Step 1

8-(3-Bromopropoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-onewas prepared from4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one(Intermediate 3) and 1,3-dibromopropane following the procedure outlinedfor Intermediate 4 (modifications: 1.0 equiv KHMDS and 5.0 equiv ofdibromide used; reaction run at room temperature). MS (ESI): 472.1.

Step 2

1-Methylpiperazine (0.5 mL, 4.5 mmol) was added to a solution of8-(3-bromopropoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(150 mg, 0.32 mmol) and DMSO (2 mL) at room temperature. After 15 h, thereaction was placed under vacuum (˜0.1 Torr, 24 h) to remove the excessamine. The resulting solution was purified by reverse-phase HPLC to give4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-2(1H)-one.¹H NMR (400 MHz, DMSO-d₆, bis HCl salt): δ 12.01 (br, 2H), 10.80 (br,1H), 9.21 (s, 1H), 8.79 (s, 2H), 8.01 (d, 1H), 7.15 (d, 1H), 4.94 (s,1H), 4.04 (t, 2H), 3.95 (s, 3H), 3.90-3.60 (br m, 4H), 3.60-3.34 (br m,6H), 2.82 (s, 3H), 2.25 (m, 2H); MS (ESI): 492.3.

EXAMPLE 194-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(3-morpholinopropoxy)quinolin-2(1H)-one

The title compound was prepared from8-(3-bromopropoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-oneand morpholine following the procedure outlined in Example 18, Step 2.¹H NMR (400 MHz, DMSO-d₆, HCl salt): δ 10.58 (br, 1H), 10.44 (s, 1H),8.94 (s, 1H), 8.77 (s, 2H), 7.93 (d, 1H), 7.09 (d, 1H), 4.82 (s, 1H),4.02 (t, 2H), 3.98 (m, 2H), 3.93 (s, 3H), 3.76 (t, 2H), 3.46 (d, 2H),3.33 (m, 2H), 3.10 (m, 2H), 2.22 (m, 2H); MS (ESI): 479.3.

EXAMPLE 204-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(7-(4-methylpiperazin-1-yl)heptyloxy)quinolin-2(1H)-one

The title compound was prepared from4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one(Intermediate 3), 1,7-dibromoheptane, and 1-methylpiperazine followingthe procedures outlined for Intermediate 4 (modifications: NMP(N-methylpyrrolidone) used as solvent and 5.0 equiv of dibromide used)and Example 18, Step 2. ¹H NMR (400 MHz, DMSO-d₆, bis HCl salt): δ 11.87(br, 2H), 10.46 (s, 1H), 9.22 (s, 1H), 8.81 (s, 2H), 8.01 (d, 1H), 7.16(d, 1H), 4.95 (s, 1H), 4.01 (t, 2H), 3.94 (s, 3H), 3.84-3.20 (br m, 8H),3.11 (m, 2H), 2.82 (s, 3H), 1.84-1.68 (m, 4H), 1.48-1.30 (m, 6H); MS(ESI): 548.3.

EXAMPLE 214-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(8-(4-methylpiperazin-1-yl)octyloxy)quinolin-2(1H)-one

The title compound was prepared from4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one(Intermediate 3), 1,8-dibromoocttane, and 1-methylpiperazine followingthe procedures outlined for Intermediate 4 (modifications: NMP used assolvent and 5.0 equiv of dibromide used) and Example 18, Step 2. ¹H NMR(400 MHz, DMSO-d₆, bis HCl salt): δ 11.89 (br, 2H), 10.49 (s, 1H), 9.24(s, 1H), 8.81 (s, 2H), 8.01 (d, 1H), 7.16 (d, 1H), 4.97 (s, 1H), 4.01(t, 2H), 3.94 (s, 3H), 3.82-3.20 (br m, 8H), 3.10 (m, 2H), 2.81 (s, 3H),1.84-1.66 (m, 4H), 1.46-1.26 (m, 8H); MS (ESI): 562.3.

EXAMPLE 224-(3,5-Dichloropyridin-4-ylamino)-7-methoxy-8-(6-(piperazin-1-yl)hexyloxy)quinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 4) and piperazine following the procedure outlined inExample 15 (modifications: 40° C., 8 h, purified by reverse-phase HPLC).¹H NMR (400 MHz, DMSO-d₆, bis HCl salt): δ 11.79 (br, 1H), 10.51 (s,1H), 9.81 (br, 1H), 9.73 (br, 1H), 9.25 (s, 1H), 8.82 (s, 2H), 8.02 (d,1H), 7.17 (d, 1H), 4.97 (s, 1H), 4.01 (t, 2H), 3.95 (s, 3H), 3.68 (br d,2H), 3.58-3.35 (br m, 4H), 3.26 (br, 2H), 3.13 (m, 2H), 1.84-1.70 (m,4H), 1.50-1.32 (m, 4H); MS (ESI): 520.4.

EXAMPLE 234-(3,5-dichloropyridin-4-ylamino)-8-(6-(4-ethylpiperazin-1-yl)hexyloxy)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 4) and 1-ethylpiperazine following the procedure outlinedin Example 18, Step 2 (modifications: 40° C., 24 h). ¹H NMR (400 MHz,DMSO-d₆, bis HCl salt): δ 12.00-11.60 (br, 2H), 10.46 (s, 1H), 9.21 (s,1H), 8.81 (s, 2H), 8.01 (d, 1H), 7.16 (d, 1H), 4.95 (s, 1H), 4.01 (t,2H), 3.95 (s, 3H), 3.84-3.35 (br m, 8H), 3.35-3.10 (br m, 4H), 1.84-1.70(m, 4H), 1.52-1.32 (m, 4H), 1.27 (t, 3H); MS (ESI): 548.5.

EXAMPLE 244-(3,5-dichloropyridin-4-ylamino)-8-(6-((2-(dimethylamino)ethyl)(methyl)amino)hexyloxy)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 4) and N¹,N¹,N²-trimethylethane-1,2-diamine following theprocedure outlined in Example 18, Step 2 (modifications: 40° C., 24 hthen 60° C., 4 h). ¹H NMR (400 MHz, DMSO-d₆, bis HCl salt): δ 10.91 (br,2H), 10.26 (s, 1H), 9.11 (s, 1H), 8.81 (s, 2H), 7.98 (d, 1H), 7.14 (d,1H), 4.90 (s, 1H), 4.01 (t, 2H), 3.94 (s, 3H), 3.63-3.42 (br m, 4H),3.25-3.00 (br m, 2H), 2.90-2.78 (m, 9H), 1.85-1.69 (m, 4H), 1.52-1.32(m, 4H); MS (ESI): 536.4.

EXAMPLE 258-(6-(1,4-Diazepan-1-yl)hexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 4) and 1,4-diazepane following the procedure outlined inExample 18, Step 2 (modifications: 40° C., 8 h). ¹H NMR (400 MHz,DMSO-d₆): δ 8.68 (s, 2H), 7.85 (d, 1H), 7.00 (d, 1H), 4.69 (s, 1H), 3.95(t, 2H), 3.88 (s, 3H), 2.79 (t, 2H), 2.74 (m, 2H), 2.60-2.52 (m, 4H),2.40 (t, 2H), 1.74 (m, 2H), 1.63 (m, 2H), 1.39 (m, 4H), 1.30 (m, 2H)[NH's not seen]; MS (ESI): 534.3.

EXAMPLE 264-(3,5-Dichloropyridin-4-ylamino)-7-methoxy-8-(6-(4-methyl-1,4-diazepan-1-yl)hexyloxy)quinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 4) and 1-methyl-1,4-diazepane following the procedureoutlined in Example 18, Step 2 (modifications: 40° C., 24 h). ¹H NMR(400 MHz, DMSO-d₆): δ 9.93 (s, 1H), 8.82 (br, 1H), 8.75 (s, 2H), 7.87(d, 1H), 7.04 (d, 1H), 4.76 (s, 1H), 3.95 (t, 2H), 3.89 (s, 3H),2.62-2.42 (m, 8H), 2.37 (t, 2H), 2.21 (s, 3H), 1.74 (m, 2H), 1.66 (m,2H), 1.38 (m, 4H), 1.29 (m, 2H); MS (ESI): 548.3.

EXAMPLE 274-(3,5-Dichloropyridin-4-ylamino)-8-(6-((3-(dimethylamino)propyl)(methyl)amino)hexyloxy)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 4) and N¹,N¹,N³-trimethylpropane-1,3-diamine following theprocedure outlined in Example 18, Step 2 (modifications: 40° C., 24 hthen 60° C., 4H). ¹H NMR (400 MHz, DMSO-d₆, bis HCl salt): δ 10.78-10.62(br, 2H), 10.33 (s, 1H), 9.17 (s, 1H), 8.81 (s, 2H), 8.00 (d, 1H), 7.15(d, 1H), 4.93 (s, 1H), 4.01 (t, 2H), 3.94 (s, 3H), 3.25-2.95 (m, 6H),2.76-2.70 (m, 9H), 2.13 (m, 2H), 1.80 (m, 2H), 1.73 (m, 2H), 1.47 (m,2H), 1.37 (m, 2H); MS (ESI): 550.5.

EXAMPLE 288-(6-Aminohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 4) and 28% ammonium hydroxide following the procedureoutlined in Example 18, Step 2 (modifications: 40° C., 24 h, then secondaliquot of NH₄OH added, then 60° C., 24 h). ¹H NMR (400 MHz, DMSO-d₆,HCl salt): δ 10.57 (s, 1H), 9.30 (s, 1H), 8.82 (s, 2H), 8.03 (d, 1H),7.94 (br, 3H), 7.18 (d, 1H), 4.99 (s, 1H), 4.01 (t, 2H), 3.95 (s, 3H),2.77 (m, 2H), 1.78 (m, 2H), 1.58 (m, 2H), 1.40 (m, 4H); MS (ESI): 451.3.

EXAMPLE 294-(3,5-Dichloropyridin-4-ylamino)-8-(6-(2-hydroxyethylamino)hexyloxy)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 4) and 2-aminoethanol following the procedure outlined inExample 18, Step 2 (modifications: 40° C., 24 h). ¹H NMR (400 MHz,DMSO-d₆): δ 8.70 (s, 2H), 7.86 (d, 1H), 7.01 (d, 1H), 4.70 (s, 1H), 4.52(br, 1H), 3.95 (t, 2H), 3.89 (s, 3H), 3.43 (t, 2H), 2.58 (t, 2H), 2.53(m, 2H), 1.74 (m, 2H), 1.48-1.28 (m, 6H) [NH's not seen]; MS (ESI):495.3.

EXAMPLE 304-(3,5-Dichloropyridin-4-ylamino)-8-(6-((2-hydroxyethyl)(methyl)amino)hexyloxy)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 4) and 2-(methylamino)ethanol following the procedureoutlined in Example 18, Step 2 (modifications: 40° C., 24 h). ¹H NMR(400 MHz, DMSO-d₆): δ 9.94 (s, 1H), 8.83 (s, 1H), 8.75 (s, 2H), 7.87 (d,1H), 7.04 (d, 1H), 4.76 (s, 1H), 4.32 (br, 1H), 3.95 (t, 2H), 3.89 (s,3H), 3.43 (m, 2H), 2.36 (t, 2H), 2.29 (t, 2H), 2.13 (s, 3H), 1.74 (m,2H), 1.39 (m, 4H), 1.29 (m, 2H); MS (ESI): 509.3.

EXAMPLE 318-(6-(Bis(2-hydroxyethyl)amino)hexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 4) and diethanolamine following the procedure outlined inExample 18, Step 2 (modifications: 40° C., 24 h then 60° C., 24 h). ¹HNMR (400 MHz, DMSO-d₆): δ 9.95 (s, 1H), 8.83 (s, 1H), 8.76 (s, 2H), 7.87(d, 1H), 7.04 (d, 1H), 4.77 (s, 1H), 4.30 (br, 2H), 3.95 (t, 2H), 3.90(s, 3H), 3.39 (m, 4H), 2.56-2.36 (m, 6H), 1.74 (m, 2H), 1.38 (m, 4H),1.28 (m, 2H); MS (ESI): 539.3.

EXAMPLE 324-(3,5-Dichloropyridin-4-ylamino)-8-(6-(3-hydroxypropylamino)hexyloxy)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 4) and 3-aminopropan-1-ol following the procedure outlinedin Example 18, Step 2 (modifications: 40° C., 24 h). ¹H NMR (400 MHz,DMSO-d₆): δ 8.67 (s, 2H), 7.85 (d, 1H), 7.00 (d, 1H), 4.68 (s, 1H), 3.95(t, 2H), 3.88 (s, 3H), 3.43 (t, 2H), 2.59 (t, 2H), 2.52 (m, 2H), 1.74(m, 2H), 1.54 (m, 2H), 1.48-1.28 (m, 6H) [NH's & OH not seen]; MS (ESI):509.3.

EXAMPLE 334-(3,5-Dichloropyridin-4-ylamino)-8-(6-((3-hydroxypropyl)(methyl)amino)hexyloxy)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 4) and 3-(methylamino)propan-1-ol following the procedureoutlined in Example 18, Step 2 (modifications: 40° C., 24 h). ¹H NMR(400 MHz, DMSO-d₆): δ 9.95 (s, 1H), 8.83 (s, 1H), 8.75 (s, 2H), 7.87 (d,1H), 7.04 (d, 1H), 4.76 (s, 1H), 4.52 (br, 1H), 3.95 (t, 2H), 3.89 (s,3H), 3.40 (t, 2H), 2.31 (t, 2H), 2.25 (t, 2H), 2.09 (s, 3H), 1.74 (m,2H), 1.52 (m, 2H), 1.39 (m, 4H), 1.29 (m, 2H); MS (ESI): 523.3.

Intermediate 54-(3,5-Dimethylpyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one

Step 1

A mixture of 4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one(500 mg, 1.92 mmol), 4-bromo-3,5-dimethylpyridine (350 mg, 1.88 mmol),Pd₂(dba)₃ (88 mg, 0.19 mmol Pd),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) (181 mg,0.38 mmol), sodium tert-butoxide (370 mg, 3.85 mmol), and toluene (20mL) was heated at 110° C. for 3 h under N₂ and then allowed to cool toroom temperature. The reaction was filtered and washed with 5% methanolin dichloromethane (500 mL×3). The filtrate was concentrated andpurified by silica gel chromatography (40:1; ethyl acetate/methanol) andthen reverse-phase HPLC to give 0.16 g of8-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-oneas white solid. MS (ESI): 366.2

Step 2

A solution of8-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(1.1 g, 3.0 mmol) and conc. HCl (6 mL) was maintained at roomtemperature for 3 h and then cooled to 0° C. This cold solution waspoured into a solution of 0.5 M pH 7 phosphate buffer (75 mL) and 10NNaOH (7.5 mL) at 0° C. The resulting mixture was stirred vigorously at0° C. for 15 min, filtered, washed with water (0° C., 75 mL), and thendried under vacuum to give 0.92 g of4-(3,5-dimethylpyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one.¹H NMR (400 MHz, DMSO-d₆): δ 9.43 (s, 1H), 9.37 (s, 1H), 8.40 (s, 2H),8.35 (s, 1H), 7.65 (d, 1H), 6.98 (d, 1H), 4.50 (s, 1H), 3.88 (s, 3H),2.12 (s, 6H); MS (ESI): 312.6.

Intermediate 68-(6-Chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

A mixture of4-(3,5-dimethylpyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one(1.46 g, 4.7 mmol), cesium carbonate (1.83 g, 5.6 mmol), and DMSO (15mL) was stirred at room temperature for 15min, and then1-bromo-6-chlorohexane (0.83 mL, 5.6 mmol) was added. After 45 min, thereaction was diluted with ethyl acetate, washed with water (×3), dried,filtered, concentrated, and then triturated with hexane/diethyl ether toremove the excess 1-bromo-6-chlorohexane. The solid residue was purifiedby silica gel chromatography (49:1→23:2; dichloromethane/methanol) togive8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one.¹H NMR (400 MHz, CDCl₃): δ 8.59 (s, 1H), 8.38 (s, 2H), 7.42 (d, 1H),6.90 (d, 1H), 6.05 (s, 1H), 5.13 (d, 1H), 4.12 (t, 2H), 3.97 (s, 3H),3.56 (t, 2H), 2.21 (s, 6H), 1.82 (m, 4H), 1.52 (m, 4H); MS (ESI): 430.3.

EXAMPLE 344-(3,5-Dimethylpyridin-4-ylamino)-7-methoxy-8-(6-(4-methylpiperazin-1-yl)hexyloxy)quinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 6) and 1-methylpiperazine following the procedure outlinedin Example 15 (modifications: 25° C., overnight). ¹H NMR (400 MHz,DMSO-d₆, bis HCl salt): δ 10.09 (s, 1H), 8.82 (s, 1H), 8.59 (s, 2H),7.88 (d, 1H), 7.06 (d, 1H), 4.99 (s, 1H), 3.98 (t, 2H), 3.91 (s, 3H),3.75-2.90 (br, 10H), 2.77 (s, 3H), 2.22 (s, 6H), 1.77 (m, 2H), 1.69 (m,2H), 1.44 (m, 2H), 1.36 (m, 2H); MS (ESI): 494.4.

EXAMPLE 354-(3,5-Dimethylpyridin-4-ylamino)-7-methoxy-8-(6-morpholinohexyloxy)quinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 6) and morpholine following the procedure outlined inExample 15 (modifications: 25° C., 16 h; then 40° C., 24 h). ¹H NMR (400MHz, DMSO-d₆): δ 9.62 (s, 1H), 8.40 (s, 1H), 8.39 (s, 2H), 7.88 (d, 1H),7.01 (d, 1H), 4.51 (s, 1H), 3.96 (t, 2H), 3.89 (s, 3H), 3.53 (m, 4H),2.29 (br, 4H), 2.22 (t, 2H), 2.13 (s, 6H), 1.74 (m, 2H), 1.39 (m, 4H),1.31 (m, 2H); MS (ESI): 481.4.

EXAMPLE 364-(3,5-Dimethylpyridin-4-ylamino)-7-methoxy-8-(6-(piperidin-1-yl)hexyloxy)quinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 6) and piperidine following the procedure outlined inExample 15 (modifications: 40° C., 18 h). ¹H NMR (400 MHz, DMSO-d₆): δ9.64 (s, 1H), 8.39 (s, 3H), 7.88 (d, 1H), 7.01 (d, 1H), 4.51 (s, 1H),3.95 (t, 2H), 3.89 (s, 3H), 2.25 (br, 4H), 2.17 (t, 2H), 2.13 (s, 6H),1.74 (m, 2H), 1.49-1.23 (m, 12H); MS (ESI): 479.4.

EXAMPLE 374-(3,5-Dimethylpyridin-4-ylamino)-7-methoxy-8-(6-(pyrrolidin-1-yl)hexyloxy)quinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 6) and pyrrolidine following the procedure outlined inExample 15 (modifications: 40° C., 18 h). ¹H NMR (400 MHz, DMSO-d₆; HClsalt): δ 10.51 (br, 1H), 9.73 (s, 1H), 8.58 (s, 1H), 8.44 (s, 2H), 7.92(d, 1H), 7.03 (d, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.90 (s, 3H), 3.46(m, 2H), 3.06 (m, 2H), 2.93 (m, 2H), 2.15 (s, 6H), 1.95 (m, 2H), 1.84(m, 2H), 1.76 (m, 2H), 1.67 (m, 2H), 1.43 (m, 2H), 1.35 (m, 2H); MS(ESI): 465.4.

EXAMPLE 388-(6-(Dimethylamino)hexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

EXAMPLE 394-(3,5-Dimethylpyridin-4-ylamino)-8-(6-((3-hydroxypropyl)(methyl)amino)hexyloxy)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 6) and 3-(methylamino)propan-1-ol following the procedureoutlined in Example 18, Step 2 (modifications: 22° C., 60 h). ¹H NMR(300 MHz, DMSO-d₆):):δ: 9.64 (s, 1H), 8.41 (s, 3H), 7.90 (d, J=9 Hz,1H), 7.04 (d, J=9 Hz, 1H), 4.54 (s, 2H), 3.98 (t, J=6.9 Hz, 2H), 3.43(t, J=6 Hz, 3H), 2.37-2.25 (4H, m), 2.14 (d, J=9.3 Hz, 8H), 1.76 (t,J=6.9 Hz, 2H), 1.37 (m, 6H). MS (ESI): 483.

EXAMPLE 404-(3,5-Dimethylpyridin-4-ylamino)-8-(6-((2-hydroxyethyl)(methyl)amino)hexyloxy)-7-methoxyquinolin-2(1H)-one

The title compound was prepared from8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one(Intermediate 6) and and 2-(methylamino)ethanol following the procedureoutlined in Example 18, Step 2 (modifications: 22° C., 60 h). ¹H NMR(300 MHz, DMSO-d₆):):δ: 9.67 (s, 1H), 8.42 (s, 3H), 7.91 (d, J=9 Hz,1H), 7.04 (s, J=7 Hz, 1H), 4.55 (s, 1H), 4.31 (s, 1H), 3.98 (t, J=6.6Hz, 5H), 3.46 (s, 2H), 2.40-2.28 (m, 4H), 2.15 (s, 9H), 1.75 (m, 2H),1.35 (m, 6H). MS (ESI) 469.

Ex- ample Name 414-(3,5-dichloropyridin-4-ylamino)-8-(4-hydroxybutoxy)-7-methoxyquinolin-2(1H)-one 424-(3,5-dichloropyridin-4-ylamino)-8-(5-hydroxypentyloxy)-7-methoxyquinolin-2(1H)-one 434-(3,5-dichloropyridin-4-ylamino)-8-(6-hydroxyhexyloxy)-7-methoxyquinolin-2(1H)-one 448-(4-(dimethylamino)butoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 458-(5-(dimethylamino)pentyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 464-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(4-(4-methylpiperazin-1-yl)butoxy)quinolin-2(1H)-one 474-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(5-(4-methylpiperazin-1-yl)pentyloxy)quinolin-2(1H)-one 484-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(4-morpholinobutoxy)quinolin-2(1H)-one 494-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(5-morpholinopentyloxy)quinolin-2(1H)-one 502-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)acetamide 514-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)butanoic acid 525-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)pentanoic acid 537-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)heptanoic acid 548-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)octanoic acid 559-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)nonanoic acid 564-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)butanamide 575-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)pentanamide 586-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanamide 597-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)heptanamide 608-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)octanamide 614-(3,5-dichloropyridin-4-ylamino)-8-isobutoxy-7-methoxyquinolin-2(1H)-one 628-(3-(1H-imidazol-1-yl)propoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 631-(6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexyl)guanidine 64(S)-2-(5-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)pentanamido)-3-hydroxypropanoic acid 656-(4-(3,5-dimethylpyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanamide 66(S)-2-(5-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)pentanamido)succinic acid 678-(3-(2H-tetrazol-5-yl)propoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 688-(4-(2H-tetrazol-5-yl)butoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 698-(5-(2H-tetrazol-5-yl)pentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 704-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(3-(2-(2-methoxyethoxy)ethoxy)propoxy)quinolin-2(1H)-one 718-(6-(2H-tetrazol-5-yl)hexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 725-(4-(3,5-dimethylpyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)pentanoic acid 736-(4-(3,5-dimethylpyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoic acid 747-(4-(3,5-dimethylpyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)heptanoic acid 758-(4-(3,5-dimethylpyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)octanoic acid 769-(4-(3,5-dimethylpyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)nonanoic acid 778-(3-(1H-imidazol-1-yl)propoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 788-(4-(1H-imidazol-1-yl)butoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 798-(5-(1H-imidazol-1-yl)pentyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 808-(6-(1H-imidazol-1-yl)hexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 814-(3,5-dimethylpyridin-4-ylamino)-8-(3-hydroxypropoxy)-7-methoxyquinolin-2(1H)-one 824-(3,5-dimethylpyridin-4-ylamino)-8-(4-hydroxybutoxy)-7-methoxyquinolin-2(1H)-one 834-(3,5-dimethylpyridin-4-ylamino)-8-(5-hydroxypentyloxy)-7-methoxyquinolin-2(1H)-one 844-(3,5-dimethylpyridin-4-ylamino)-8-(6-hydroxyhexyloxy)-7-methoxyquinolin-2(1H)-one 858-(3-(2H-tetrazol-5-yl)propoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 868-(4-(2H-tetrazol-5-yl)butoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 878-(5-(2H-tetrazol-5-yl)pentyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 888-(6-(2H-tetrazol-5-yl)hexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 894-(4-(3,5-dimethylpyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)butanamide 905-(4-(3,5-dimethylpyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)pentanamide 917-(4-(3,5-dimethylpyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)heptanamide 928-(4-(3,5-dimethylpyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)octanamide 939-(4-(3,5-dimethylpyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)nonanamide 942-(5-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)pentanamido)acetic acid 95(S)-2-(5-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)pentanamido)-3-(1H-imidazol-4- yl)propanoicacid 96 4-(3,5-dichloropyridin-4-ylamino)-8-(3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propoxy)-7-methoxyquinolin- 2(1H)-one 978-(2,5,8,11-tetraoxatetradecan-14-yloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 984-(3,5-dichloropyridin-4-ylamino)-8-(3-(2-(2-hydroxyethoxy)ethoxy)propoxy)-7-methoxyquinolin-2(1H)-one

The following compounds can generally be made using the methodsdescribed above. It is expected that these compounds when made will haveactivity similar to those that have been made in the examples above.

The following compounds are represented herein using the SimplifiedMolecular Input Line Entry System, or SMILES. SMILES is a modernchemical notation system, developed by David Weininger and DaylightChemical Information Systems, Inc., that is built into all majorcommercial chemical structure drawing software packages. Software is notneeded to interpret SMILES text strings, and an explanation of how totranslate SMILES into structures can be found in Weininger, D., J. Chem.Inf. Comput. Sci. 1988, 28, 31-36. All SMILES strings used herein, aswell as numerous IUPAC names, were generated using eitherCambridgeSoft's ChemDraw 10.0 or ChemBioDraw Ultra 11.0.

-   COc1ccc2c(cc(═O)[nH]c2c1OCCCCC(═O)O)Nc1c(C)cncc1C-   COc1ccc2c(cc(═O)[nH]c2c1OCCCCN1CCN(C)CC1)Nc1c(C)cncc1C-   COc1ccc2c(cc(═O)[nH]c2c1OCCCCN1CCOCC1)Nc1c(C)cncc1C-   COc1ccc2c(cc(═O)[nH]c2c1OCCCCCC(═O)O)Nc1c(C)cncc1C-   COc1ccc2c(cc(═O)[nH]c2c1OCC(═O)N)Nc1c(C)cncc1C-   COc1ccc2c(cc(═O)[nH]c2c1OCCCCC(═O)N)Nc1c(C)cncc1C-   COc1ccc2c(cc(═O)[nH]c2c1OCCCCCCC(═O)O)Nc1c(C)cncc1C-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(C)cncc3C-   CNCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCN)Nc3c(C)cncc3C-   Cc1cncc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N)Nc3c(C)cncc3C-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(C)cncc3F-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cncc3F-   Cc1cncc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cncc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(F)cncc3F-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(F)cncc3F-   NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3F-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(F)cncc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(C)cccc3C-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCN)c(OCF)ccc23-   CNCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3C-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCN)Nc3c(C)cccc3C-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cccc3C-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N)Nc3c(C)cccc3C-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(C)cccc3F-   CNCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3F-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCN)Nc3c(C)cccc3F-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cccc3F-   Cc1cccc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N)Nc3c(C)cccc3F-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cccc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cc(F)cc3C-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cc(F)cc3F-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(C)cc(O)cc3C-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cc(O)cc3C-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(C)cc(O)cc3F-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN)Nc3c(F)cccc3F-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(F)cccc3F-   NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(F)cccc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(F)cc(F)cc3F-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N)Nc3c(F)cc(O)cc3F-   CN(C)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3C-   CCCN(C)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3C-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCn4cccn4)c(OC(F)(F)F)ccc23-   COCCOCCOCCOCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3C-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCCN)c(OC(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCn3ccnc3)Nc4c(C)cccc4C-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCCCNC(═N)N)c(OC(F)(F)F)ccc23-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCCC4)c(OC(F)F)ccc23-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCCCn4ccnn4)c(OCF)ccc23-   CC(C)[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3C)C(═O)O-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](Cc4ccccc4)C(═O)O)c(OC(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](CCSC)C(═O)O)Nc3c(C)cccc3C-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OC(F)(F)F)ccc23-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCC(═O)NCC(═O)O)c(OC(F)(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(C)cccc3C-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CCCCN)C(═O)O)c(OCF)ccc23-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](Cc4cnc[nH]4)C(═O)O)c(OC(F)F)ccc23-   CN1CCN(CC1)C(═O)CCCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C)cccc4C-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](Cc4ccc(O)cc4)C(═O)O)c(OCF)ccc23-   Cc1cccc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](Cc4ccc(O)cc4)C(═O)O)c(OC(F)F)ccc23-   CCNCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3F-   CCN(C)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3F-   COCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3F-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCNC(═N)N)Nc3c(C)cccc3F-   Cc1cccc(F)c1NC2=CC(═O)Nc3c(OCCCCCn4cnnc4)c(OC(F)F)ccc23-   Cc1cccc(F)c1NC2=CC(═O)Nc3c(OCCCCCOc4ccncc4)c(OCF)ccc23-   CCNCCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3F-   Cc1c ccc(F)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCC(F)C4)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCCOc3cccnc3)Nc4c(C)cccc4F-   Cc1cccc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OC(F)(F)F)ccc23-   CN(C)CCOC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3F-   Cc1cccc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)F)ccc23-   Cc1cccc(F)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](Cc4c[nH]c5ccccc45)C(═O)O)c(OCF)ccc23-   Cc1cccc(F)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](Cc4c[nH]c5ccccc45)C(═O)O)c(OC(F)F)ccc23-   Cc1cccc(F)c1NC2=CC(═O)Nc3c(OCCCCC(═O)OCC[N+](C)(C)C)c(OC(F)(F)F)ccc23-   CC(C)[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3F)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(C)cccc3F-   Cc1cccc(F)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N)c(OCF)ccc23-   CN1CCN(CC1)C(═O)CCCCCOc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C)cccc4F-   CC[C@H](C)[C@H](NC(═O)CCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3F)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCOCC3)Nc4c(C)cccc4C1-   Cc1cccc(C1)c1NC2=CC(═O)Nc3c(OCCCCN4CCC(F)CC4)c(OC(F)F)ccc23-   Cc1cccc(C1)c1NC2=CC(═O)Nc3c(OCCCCOc4ccccn4)c(OC(F)(F)F)ccc23-   Cc1cccc(C1)c1NC2=CC(═O)Nc3c(OCCCCCNC(═N)N)c(OCF)ccc23-   CCCCCN(C)CCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3C1-   Cc1cccc(C1)c1NC2=CC(═O)Nc3c(OCCCCCOc4cccnc4)c(OC(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCCN)Nc3c(C)cccc3C1-   Cc1cccc(C1)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCOCC4)c(OC(F)(F)F)ccc23-   COCCOCCOCCCCCCOc1c2NC(═O)C═C(Nc3c(C)cccc3C1)c2ccc1OC(F)F-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](C(C)C)C(═O)O)Nc3c(C)cccc3C1-   CC(C)C[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3C1)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](Cc3c[nH]c4ccccc34)C(═O)O)Nc5c(C)cccc5C1-   Cc1cccc(C1)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OCF)ccc23-   CC(C)[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3C1)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)Nc3c(C)cccc3C1-   CC(C)C[C@H](NC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3C1)C(═O)O-   Cc1cccc(Br)c1NC2=CC(═O)Nc3c(OCCCCN)c(OC(F)F)ccc23-   COCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3Br-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCC(F)C3)Nc4c(C)cccc4Br-   Cc1cccc(Br)c1NC2=CC(═O)Nc3c(OCCCCCN4CCCC(F)C4)c(OC(F)F)ccc23-   Cc1cccc(Br)c1NC2=CC(═O)Nc3c(OCCCCCn4cccc4)c(OC(F)(F)F)ccc23-   CCCNCCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3Br-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCCn3cnnn3)Nc4c(C)cccc4Br-   COCCOCCOCCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3Br-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](CO)C(═O)O)Nc3c(C)cccc3Br-   Cc1cccc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CCCCN)C(═O)O)c(OC(F)F)ccc23-   Cc1cccc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CCC(═O)O)C(═O)O)c(OCF)ccc23-   CN(C)CCN(C)C(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3Br-   CN1CCN(CC1)C(═O)CCCOc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C)cccc4Br-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](CO)C(═O)O)Nc3c(C)cccc3Br-   CN(C)CCCN(C)C(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3Br-   CN(CCC[N+](C)(C)C)C(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3Br-   CN(CCC[N+](C)(C)C)C(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cccc3Br-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](Cc3ccc(O)cc3)C(═O)O)Nc4c(C)cccc4Br-   CCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3C-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCCCC3)Nc4c(C)cc(F)cc4C-   Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCN4CCCC4)c(OCF)ccc23-   CCCCCN(C)CCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3C-   Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCn4nccn4)c(OC(F)F)ccc23-   Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCOc4ccncc4)c(OC(F)(F)F)ccc23-   Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCCn4ccnc4)c(OC(F)F)ccc23-   Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCC(═O)OCC[N+](C)(C)C)c(OCF)ccc23-   CN(C)CCCN(C)C(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3C-   Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCC(═O)OCC[N+](C)(C)C)c(OC(F)(F)F)ccc23-   Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N4CCC[C@H]4C(═O)O)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N(C)CCN(C)C)Nc3c(C)cc(F)cc3C-   Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N4CCC[C@I-1]4C(═O)O)c(OC(F)(F)F)ccc23-   Cc1cc(F)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](Cc4ccccc4)C(═O)O)c(OCF)ccc23-   Cc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCn4cnnn4)c(OC(F)F)ccc23-   Cc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCOc4ccncc4)c(OC(F)(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCO[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)Nc4c(C)cc(F)cc4F-   CCCCN(C)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3F-   Cc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCOc4ccncc4)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCCN)Nc3c(C)cc(F)cc3F-   COCCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3F-   Cc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCCC4)c(OCF)ccc23-   Cc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCCn4nccn4)c(OC(F)F)ccc23-   CC(C)C[C@H](NC(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3F)C(═O)O-   CC(C)[C@H](NC(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3F)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(C)cc(F)cc3F-   CN(C)CCN(C)C(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3F-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N3CCNCC3)Nc4c(C)cc(F)cc4F-   Cc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](Cc4ccc(O)cc4)C(═O)O)c(OCF)ccc23-   Cc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CCC(═O)N)C(═O)O)c(OC(F)(F)F)ccc23-   CC(C)[C@H](NC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3F)C(═O)O-   Cc1cc(F)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](Cc4ccccc4)C(═O)O)c(OCF)ccc23-   CCCCN(C)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCn3ccnc3)Nc4c(C)cc(F)cc4C1-   Cc1cc(F)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCOc4cccnc4)c(OC(F)(F)F)ccc23-   COCCN(C)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3C1-   Cc1cc(F)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCCn4ncnn4)c(OC(F)(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCOc3cccnc3)Nc4c(C)cc(F)cc4C1-   Cc1cc(F)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCCOc4ccncc4)c(OC(F)F)ccc23-   CCCCN(C)CCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3C1-   Cc1cc(F)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCC(F)C4)c(OCF)ccc23-   Cc1cc(F)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCCCn4cccc4)c(OC(F)F)ccc23-   Cc1cc(F)cc(C1)c1NC2=CC(═O)Nc3c(OCC(═O)NCC(═O)O)c(OC(F)(F)F)ccc23-   Cc1cc(F)cc(C1)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CO)C(═O)O)c(OCF)ccc23-   CN(CCC[N+](C)(C)C)C(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(C)cc(F)cc3C1-   Cc1cc(F)cc(C1)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](CCCCN)C(═O)O)c(OC(F)F)ccc23-   Cc1cc(F)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CO)C(═O)O)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H]([C@@H](C)O)C(═O)O)Nc3c(C)cc(F)cc3C1-   Cc1cc(F)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CCCCN)C(═O)O)c(OC(F)(F)F)ccc23-   Cc1cc(F)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OC(F)F)ccc23-   Cc1cc(F)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)OCC[N+](C)(C)C)c(OCF)ccc23-   Cc1cc(F)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)(F)F)ccc23-   COCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3Br-   Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCn4ccnn4)c(OC(F)F)ccc23-   CCCCCN(C)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3Br-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCC(F)CC3)Nc4c(C)cc(F)cc4Br-   COCCOCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(F)cc3Br-   Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCC(F)(F)C4)c(OC(F)(F)F)ccc23-   Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCn4ccnc4)c(OC(F)F)ccc23-   Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@I-1](CCC(═O)O)C(═O)O)c(OC(F)(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](CCC(═O)N)C(═O)O)Nc3c(C)cc(F)cc3Br-   Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCC(═O)OCC[N+](C)(C)C)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(C)cc(F)cc3Br-   Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CCCCN)C(═O)O)c(OC(F)F)ccc23-   Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CCCCN)C(═O)O)c(OC(F)(F)F)ccc23-   Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)OCC[N+](C)(C)C)c(OCF)ccc23-   Cc1cc(F)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)Nc3c(C)cc(F)cc3Br-   CCCNCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C-   Cc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCCCCN4CCC(F)(F)C4)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCn3cnnc3)Nc4c(C)cc(O)cc4C-   CCCNCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C-   Cc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCn4cncn4)c(OC(F)(F)F)ccc23-   Cc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCn4cnnn4)c(OC(F)F)ccc23-   Cc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCOc4ccncc4)c(OCF)ccc23-   COCCN(C)CCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C-   Cc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCOCC4)c(OC(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCCN3CCCCC3)Nc4c(C)cc(O)cc4C-   Cc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CC(═O)O)C(═O)O)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](CC(═O)N)C(═O)O)Nc3c(C)cc(O)cc3C-   CN(C)CCCN(C)C(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C-   CN(CCC[N+](C)(C)C)C(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C-   C[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C)C(=O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](Cc3ccccc3)C(═O)O)Nc4c(C)cc(O)cc4C-   Cc1cc(O)cc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)(F)F)ccc23-   Cc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCCCCn4cccn4)c(OCF)ccc23-   COCCOCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3F-   CCCN(C)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3F-   Cc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCn4cccn4)c(OC(F)F)ccc23-   Cc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCn4ncnn4)c(OC(F)(F)F)ccc23-   CNCCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3F-   COCCOCCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3F-   Cc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OC(F)(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](CC(C)C)C(═O)O)Nc3c(C)cc(O)cc3F-   Cc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CO)C(═O)O)c(OCF)ccc23-   Cc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCCCC(═O)N4CCNCC4)c(OC(F)F)ccc23-   CN1CCN(CC1)C(═O)CCCOc2c(OCF)ccc3C(═CC(═O)Nc23)Nc4c(C)cc(O)cc4F-   Cc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OC(F)(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N3CCNCC3)Nc4c(C)cc(O)cc4F-   CC(C)[C@H](NC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3F)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)NCC[N+](C)(C)C)Nc3c(C)cc(O)cc3F-   Cc1cc(O)cc(F)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](Cc4ccc(O)cc4)C(═O)O)c(OC(F)F)ccc23-   CCN(CC)CCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C1-   Cc1cc(O)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCN4CCCCC4)c(OC(F)(F)F)ccc23-   Cc1cc(O)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCN4CCC(F)C4)c(OC(F)F)ccc23-   CCNCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C1-   CCCN(C)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCn3cnnc3)Nc4c(C)cc(O)cc4C1-   Cc1cc(O)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCCOCCOCCOCCO)c(OC(F)(F)F)ccc23-   CCN(CC)CCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C1-   Cc1cc(O)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCCCn4ccnc4)c(OCF)ccc23-   Cc1cc(O)cc(C1)c1NC2=CC(═O)Nc3c(OCC(═O)OCC[N+](C)(C)C)c(OC(F)F)ccc23-   Cc1cc(O)cc(C1)c1NC2=CC(═O)Nc3c(OCC(═O)N4CCC[C@H]4C(═O)O)c(OCF)ccc23-   C[C@H](NC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C1)C(═O)O-   C[C@@H](O)[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C1)C(═O)O-   CN(CCC[N+](C)(C)C)C(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3C1-   Cc1cc(O)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N4CCNCC4)c(OC(F)F)ccc23-   Cc1cc(O)cc(C1)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](CC(═O)N)C(═O)O)Nc3c(C)cc(O)cc3C1-   Cc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCn4nccn4)c(OC(F)(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCOCCOCCOCCO)Nc3c(C)cc(O)cc3Br-   Cc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCn4cnnc4)c(OC(F)F)ccc23-   Cc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCOc4ccccn4)c(OC(F)(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCOc3ccncc3)Nc4c(C)cc(O)cc4Br-   CCN(C)CCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3Br-   Cc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCn4ncnn4)c(OCF)ccc23-   Cc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCOCCOCCOCCO)c(OC(F)(F)F)ccc23-   CC[C@H](C)[C@H](NC(═O)COc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3Br)C(═O)O-   Cc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](Cc4ccc(O)cc4)C(═O)O)c(OCF)ccc23-   Cc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OC(F)(F)F)ccc23-   Cc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCC(═O)N4CCC[C@H]4C(═O)O)c(OC(F)F)ccc23-   CN(C)CCN(C)C(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(O)cc3Br-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CC(═O)O)C(═O)O)Nc3c(C)cc(O)cc3Br-   Cc1cc(O)cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OCF)ccc23-   Cc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCn4cncn4)c(OC(F)F)ccc23)C(═O)O-   Cc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCn4cnnc4)c(OC(F)(F)F)ccc23)C(═O)O-   Cc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCOCCO)c(OCF)ccc23)C(═O)O-   COCCOCCOCCOCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C)C(═O)O-   Cc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCCn4cccn4)c(OC(F)F)ccc23)C(═O)O-   Cc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCCn4ncnn4)c(OCF)ccc23)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCOc3ccncc3)Nc4c(C)cc(cc4C)C(═O)O-   Cc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCOCC4)c(OC(F)F)ccc23)C(═O)O-   Cc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCCCCOCCO)c(OC(F)(F)F)ccc23)C(═O)O-   CN(C)CCNC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N(C)CCCN(C)C)Nc3c(C)cc(cc3C)C(═O)O-   Cc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N4CCNCC4)c(OC(F)F)ccc23)C(═O)O-   Cc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)(F)F)ccc23)C(═O)O-   Cc1cc(cc(C)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OC(F)F)ccc23)C(═O)O-   C[C@@H](O)[C@H](NC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C)C(═O)O)C(═O)O-   CN(C)CCOC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C)C(═O)O-   CN(C)CCNC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C)C(═O)O-   Cc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCCCCN4CCCC(F)(F)C4)c(OCF)ccc23)C(═O)O-   Cc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCCCCOc4ccccn4)c(OC(F)F)ccc23)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCOc3cccnc3)Nc4c(C)cc(cc4F)C(═O)O-   Cc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCCCCCOc4ccncc4)c(OC(F)F)ccc23)C(═O)O-   CCCNCCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3F)C(═O)O-   Cc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCCCCCCn4cnnc4)c(OC(F)(F)F)ccc23)C(═O)O-   Cc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCCCCCCOc4ccccn4)c(OCF)ccc23)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCCOc3ccncc3)Nc4c(C)cc(cc4F)C(═O)O-   Cc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N)c(OC(F)F)ccc23)C(═O)O-   Cc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](Cc4ccc(O)cc4)C(═O)O)c(OCF)ccc23)C(═O)O-   CN(CC[N+](C)(C)C)C(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3F)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CC(C)C)C(═O)O)Nc3c(C)cc(cc3F)C(═O)O-   Cc1cc(cc(F)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N4CCC[C@M4C(═O)O)c(OC(F)(F)F)ccc23)C(═O)O-   CN(CC[N+](C)(C)C)C(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3F)C(═O)O-   CN(CC[N+](C)(C)C)C(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3F)C(═O)O-   CC[C@H](C)[C@H](NC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3F)C(═O)O)C(═O)O-   CCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C1)C(═O)O-   CCCCCN(C)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C1)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCCC3)Nc4c(C)cc(cc4C1)C(═O)O-   Cc1cc(cc(C1)c1NC2=CC(═O)Nc3c(OCCCCn4cnnc4)c(OCF)ccc23)C(═O)O-   Cc1cc(cc(C1)c1NC2=CC(═O)Nc3c(OCCCCCn4cccc4)c(OCF)ccc23)C(═O)O-   Cc1cc(cc(C1)c1NC2=CC(═O)Nc3c(OCCCCCn4cncn4)c(OC(F)(F)F)ccc23)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCn3cnnn3)Nc4c(C)cc(cc4C1)C(═O)O-   CN(C)CCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C1)C(═O)O-   CCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C1)C(═O)O-   COCCOCCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C1)C(═O)O-   Cc1cc(cc(C1)c1NC2=CC(═O)Nc3c(OCCCCCCOCCOCCOCCO)c(OC(F)F)ccc23)C(=O)O-   CN(CC[N+](C)(C)C)C(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C1)C(═O)O-   Cc1cc(cc(C1)c1NC2=CC(═O)Nc3c(OCCCC(═O)N4CCNCC4)c(OC(F)F)ccc23)C(═O)O-   Cc1cc(cc(C1)c1NC2=CC(═O)Nc3c(OCCCCC(═O)NCC(═O)O)c(OC(F)F)ccc23)C(═O)O-   Cc1cc(cc(C1)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](Cc4ccccc4)C(═O)O)c(OCF)ccc23)C(═O)O-   CSCC[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3C1)C(═O)O)C(═O)O-   CN1CCN(CC1)C(═O)CCCCCOc2c(OCF)ccc3C(═CC(═O)Nc23)Nc4c(C)cc(cc4C1)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](CO)C(═O)O)Nc3c(C)cc(cc3C1)C(═O)O-   CN(C)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3Br)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCOCC3)Nc4c(C)cc(cc4Br)C(═O)O-   Cc1cc(cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCOCCOCCO)c(OCF)ccc23)C(═O)O-   Cc1cc(cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCN)c(OC(F)F)ccc23)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCCN3CCCC3)Nc4c(C)cc(cc4Br)C(═O)O-   Cc1cc(cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCn4cnnn4)c(OC(F)(F)F)ccc23)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](Cc3c[nH]c4ccccc34)C(═O)O)Nc5c(C)cc(cc5Br)C(═O)O-   Cc1cc(cc(Br)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](Cc4c[nH]c5ccccc45)C(═O)O)c(OCF)ccc23)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N3CCN(C)CC3)Nc4c(C)cc(cc4Br)C(═O)O-   Cc1cc(cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N)c(OC(F)F)ccc23)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)NCC(═O)O)Nc3c(C)cc(cc3Br)C(═O)O-   C[C@H](NC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cc(cc3Br)C(═O)O)C(═O)O-   Cc1cc(cc(Br)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)(F)F)ccc23)C(═O)O-   CCN(CC)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F-   NC(═N)NCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F-   COc1ccc2C(═CC(═O)Nc2c1OCCCCOCCOCCOCCO)Nc3c(F)cccc3F-   FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCOCC3)Nc4c(F)cccc4F-   FC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCn3ccnn3)Nc4c(F)cccc4F-   COCCOCCOCCCCCOc1c2NC(═O)C═C(Nc3c(F)cccc3F)c2ccc1OC(F)(F)F-   FC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCCn3ccnc3)Nc4c(F)cccc4F-   COCCOCCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F-   NCCCC[C@H](NC(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F)C(═O)O-   NC(═N)NCCC[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F)C(═O)O-   NC(═O)CC[C@H](NC(═O)COc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F)C(═O)O-   NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N3CCNCC3)Nc4c(F)cccc4F-   NC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F-   C[N+](C)(C)CCNC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F-   C[N+](C)(C)CCNC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N(C)CC[N+](C)(C)C)Nc3c(F)cccc3F-   NCCCC[C@H](NC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3F)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](Cc3cnc[nH]3)C(═O)O)Nc4c(F)cccc4F-   NCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3C1-   Fc1cccc(C1)c1NC2=CC(═O)Nc3c(OCCCCn4nccn4)c(OC(F)(F)F)ccc23-   COCCOCCOCCOCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCN(C)C)Nc3c(F)cccc3C1-   Fc1cccc(C1)c1NC2=CC(═O)Nc3c(OCCCCCN4CCCC(F)(F)C4)c(OC(F)(F)F)ccc23-   FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCOc3ccccn3)Nc4c(F)cccc4C1-   OCCOCCOCCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3C1-   CN(CCC[N+](C)(C)C)C(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3C1-   CN1CCN(CC1)C(═O)COc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(F)cccc4C1-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(F)cccc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](C)C(═O)O)Nc3c(F)cccc3C1-   OC(═O)[C@H](Cc1ccc(O)cc1)NC(═O)CCCOc2c(OCF)ccc3C(═CC(═O)Nc23)Nc4c(F)cccc4C1-   C[C@@H](O)[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3C1)C(═O)O-   CN(CC[N+](C)(C)C)C(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3C1-   OC(═O)CNC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3C1-   C[C@@H](O)[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cccc3C1)C(═O)O-   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OC(═O)[C@H](Cc1cnc[nH]1)NC(═O)CCCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Br)cc(O)cc4Br-   CNCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)O-   CCN(C)CCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)O-   OC(═O)c1cc(Br)c(NC2=CC(═O)Nc3c(OCCCCN4CCC(F)C4)c(OC(F)(F)F)ccc23)c(Br)c1-   OC(═O)c1cc(Br)c(NC2=CC(═O)Nc3c(OCCCCCN4CCCC(F)(F)C4)c(OCF)ccc23)c(Br)c1-   OC(═O)c1cc(Br)c(NC2=CC(═O)Nc3c(OCCCCCn4cnnn4)c(OC(F)F)ccc23)c(Br)c1-   COCCOCCOCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)O-   CNCCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)O-   COCCN(C)CCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCCN3CCCC(F)(F)C3)Nc4c(Br)cc(cc4Br)C(═O)O-   OCCOCCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)O-   CN(C)CCNC(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)O-   OC(═O)c1cc(Br)c(NC2=CC(═O)Nc3c(OCCCC(═O)N4CCNCC4)c(OC(F)F)ccc23)c(Br)c1-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](CO)C(═O)O)Nc3c(Br)cc(cc3Br)C(═O)O-   CN(C)CCNC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)O-   CN(CC[N+](C)(C)C)C(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)O-   C[C@H](NC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Br)cc(cc3Br)C(═O)O)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(Br)cc(cc3Br)C(═O)O-   CCN(CC)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C-   CCCCN(C)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCCC(F)(F)C3)Nc4c(C)cncc4C-   Cc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCCn4nccn4)c(OC(F)F)ccc23-   Cc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCCn4cncn4)c(OC(F)(F)F)ccc23-   CNCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C-   COCCN(C)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCC(F)CC3)Nc4c(C)cncc4C-   Cc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCCCn4nccn4)c(OC(F)(F)F)ccc23-   Cc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCCCOc4cccnc4)c(OC(F)F)ccc23-   CCNCCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C-   CCN(C)CCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C-   CCCCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C-   C[C@H](NC(═O)COc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C)C(═O)O-   Cc1cncc(C)c1NC2=CC(═O)Nc3c(OCC(═O)N4CCC[C@I-1]4C(═O)O)c(OC(F)(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](Cc3ccccc3)C(═O)O)Nc4c(C)cncc4C-   C[C@@H](O)[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C)C(═O)O-   Cc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCC(═O)OCC[N+](C)(C)C)c(OC(F)F)ccc23-   CN(CC[N+](C)(C)C)C(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C-   CN(C)CCCN(C)C(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N3CCN(C)CC3)Nc4c(C)cncc4C-   Cc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N)c(OC(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N3CCNCC3)Nc4c(C)cncc4C-   Cc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CO)C(═O)O)c(OCF)ccc23-   C[C@@H](O)[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C)C(═O)O-   Cc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N4CCNCC4)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)NCC(═O)O)Nc3c(C)cncc3C-   Cc1cncc(C)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N4CCC[C@M4C(═O)O)c(OC(F)F)ccc23-   CSCC[C@H](NC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C)C(═O)O-   Cc1cncc(F)c1NC2=CC(═O)Nc3c(OCCCCN4CCCCC4)c(OC(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCC(F)(F)CC3)Nc4c(C)cncc4F-   COCCOCCOCCOCCCCOc1c2NC(═O)C═C(Nc3c(C)cncc3F)c2ccc1OCF-   COCCOCCOCCOCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3F-   CN(C)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3F-   Cc1cncc(F)c1NC2=CC(═O)Nc3c(OCCCCCN4CCC(F)(F)CC4)c(OCF)ccc23-   Cc1cncc(F)c1NC2=CC(═O)Nc3c(OCCCCCn4cccn4)c(OC(F)(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCOCCO)Nc3c(C)cncc3F-   CNCCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3F-   CCN(CC)CCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3F-   Cc1cncc(F)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCCC4)c(OC(F)(F)F)ccc23-   COCCOCCOCCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3F-   Cc1cncc(F)c1NC2=CC(═O)Nc3c(OCC(═O)OCC[N+](C)(C)C)c(OCF)ccc23-   CN1CCN(CC1)C(═O)COc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C)cncc4F

COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](C(C)C)C(═O)O)Nc3c(C)cncc3F

-   Cc1cncc(F)c1NC2=CC(═O)Nc3c(OCC(═O)N[C@@H](Cc4c[nH]c5ccccc45)C(═O)O)c(OC(F)(F)F)ccc23-   Cc1cncc(F)c1NC2=CC(═O)Nc3c(OCCCC(═O)NCC[N+](C)(C)C)c(OC(F)F)ccc23-   CN1CCN(CC1)C(═O)CCCOc2c(OCF)ccc3C(═CC(═O)Nc23)Nc4c(C)cncc4F-   CN1CCN(CC1)C(═O)CCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C)cncc4F-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](C)C(═O)O)Nc3c(C)cncc3F-   CN(C)CCN(C)C(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3F-   CN(CC[N+](C)(C)C)C(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3F-   CN1CCN(CC1)C(═O)CCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C)cncc4F-   CSCC[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3F)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CCC(═O)N)C(═O)O)Nc3c(C)cncc3F-   CN(C)CCN(C)C(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3F-   Cc1cncc(F)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CO)C(═O)O)c(OCF)ccc23-   Cc1cncc(F)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](CO)C(═O)O)c(OC(F)(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](CCCCN)C(═O)O)Nc3c(C)cncc3F-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCN4CCOCC4)c(OC(F)(F)F)ccc23-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCN4CCC(F)CC4)c(OC(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCC(F)(F)C3)Nc4c(C)cncc4C1-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCOc4cccnc4)c(OCF)ccc23-   CCN(CC)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C1-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCCn4ccnc4)c(OC(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCn3ccnn3)Nc4c(C)cncc4C1-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCCOc4ccncc4)c(OCF)ccc23-   CNCCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C1-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCC(F)(F)C4)c(OC(F)(F)F)ccc23-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCCCOc4ccncc4)c(OC(F)F)ccc23-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCCCOCCO)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)OCCN(C)C)Nc3c(C)cncc3C1-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCC(═O)OCC[N+](C)(C)C)c(OC(F)F)ccc23-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCC(═O)OCC[N+](C)(C)C)c(OC(F)(F)F)ccc23-   C[C@@H](O)[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C1)C(═O)O-   CN(C)CCCN(C)C(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C1-   CN(CCC[N+](C)(C)C)C(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](C(C)C)C(═O)O)Nc3c(C)cncc3C1-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCC(═O)N[C@@H](CCC(═O)N)C(═O)O)c(OCF)ccc23-   CN(C)CCNC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)NCC[N+](C)(C)C)Nc3c(C)cncc3C1-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)c(OCF)ccc23-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCC(═O)N[C@@H](CC(═O)O)C(═O)O)c(OC(F)F)ccc23-   CN(C)CCOC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C1-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)NCC(═O)O)c(OCF)ccc23-   C[C@H](NC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3C1)C(═O)O-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](Cc4c[nH]c5ccccc45)C(═O)O)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](Cc3cnc[nH]3)C(═O)O)Nc4c(C)cncc4C1-   Cc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCCC(═O)N[C@@H](Cc4cnc[nH]4)C(═O)O)c(OC(F)F)ccc23-   Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCN4CCCC(F)C4)c(OC(F)(F)F)ccc23-   Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCN4CCCC(F)(F)C4)c(OC(F)F)ccc23-   Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCN4CCC(F)(F)C4)c(OCF)ccc23-   Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCOc4ccncc4)c(OCF)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCOCCO)Nc3c(C)cncc3Br-   CN(C)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3Br-   CCN(CC)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3Br-   CCCCCN(C)CCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3Br-   Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCCN4CCOCC4)c(OC(F)(F)F)ccc23-   COCCOCCOCCOCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3Br-   Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCC(F)CC4)c(OCF)ccc23-   Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCC(F)(F)C4)c(OC(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCCn3ccnn3)Nc4c(C)cncc4Br-   Cc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCOc4ccncc4)c(OC(F)F)ccc23-   COCCOCCOCCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C)cncc3Br-   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COc1ccc2C(═CC(═O)Nc2c1OCCCCCCn3cccc3)Nc4c(F)cncc4C1-   Fc1cncc(C1)c1NC2=CC(═O)Nc3c(OCCCCCCOc4cccnc4)c(OC(F)(F)F)ccc23-   COCCOCCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3C1-   C[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3C1)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](CC(C)C)C(═O)O)Nc3c(F)cncc3C1-   NCCCC[C@H](NC(═O)COc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3C1)C(═O)O-   NC(═N)NCCC[C@H](NC(═O)COc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3C1)C(═O)O-   NC(═N)NCCC[C@H](NC(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3C1)C(═O)O-   CN(C)CCN(C)C(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](C)C(═O)O)Nc3c(F)cncc3C1-   OC(═O)[C@@H]1CCCN1C(═O)CCCOc2c(OCF)ccc3C(═CC(═O)Nc23)Nc4c(F)cncc4C1-   NC(═O)C[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3C1)C(═O)O-   OC(═O)[C@@H]1CCCN1C(═O)CCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(F)cncc4C1-   OC(═O)[C@H](Cc1ccccc1)NC(═O)CCCCOc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(F)cncc4C1-   OC(═O)[C@H](Cc1cnc[nH]1)NC(═O)CCCCOc2c(OCF)ccc3C(═CC(═O)Nc23)Nc4c(F)cncc4C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CC(═O)N)C(═O)O)Nc3c(F)cncc3C1-   NC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](CC(C)C)C(═O)O)Nc3c(F)cncc3C1-   OC(═O)[C@H](Cc1c[nH]c2ccccc12)NC(═O)CCCCCOc3c(OC(F)(F)F)ccc4C(═CC(═O)Nc34)Nc5c(F)cncc5C1-   OC(═O)C[C@H](NC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3C1)C(═O)O-   Fc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCN4CCCCC4)c(OC(F)(F)F)ccc23-   COc1ccc2C(═CC(═O)Nc2c1OCCCCn3nccn3)Nc4c(F)cncc4Br-   COCCOCCOCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br-   OCCOCCOCCOCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCN(C)C)Nc3c(F)cncc3Br-   Fc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCCN4CCCC4)c(OC(F)(F)F)ccc23-   FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCC(F)(F)C3)Nc4c(F)cncc4Br-   FC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCOc3ccncc3)Nc4c(F)cncc4Br-   OCCOCCOCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br-   NCCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCCNC(═N)N)Nc3c(F)cncc3Br-   Fc1cncc(Br)c1NC2=CC(═O)Nc3c(OCCCCCCN4CCCCC4)c(OC(F)(F)F)ccc23-   FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCCOc3ccncc3)Nc4c(F)cncc4Br-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)NCC[N+](C)(C)C)Nc3c(F)cncc3Br-   CC(C)C[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)O-   CC[C@H](C)[C@H](NC(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)O-   OC(═O)[C@H](Cc1ccccc1)NC(═O)COc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(F)cncc4Br-   NCCCC[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)O-   CN(CC[N+](C)(C)C)C(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br-   CC(C)[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](CCCNC(═N)N)C(═O)O)Nc3c(F)cncc3Br-   NC(═O)C[C@H](NC(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N(C)CCC[N+](C)(C)C)Nc3c(F)cncc3Br-   C[C@H](NC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)O-   C[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)O-   CC(C)C[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br)C(═O)O-   C[N+](C)(C)CCOC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br-   CN(C)CCNC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)NCC[N+](C)(C)C)Nc3c(F)cncc3Br-   C[N+](C)(C)CCNC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(F)cncc3Br-   CN(C)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCOCCO)Nc3c(C1)cncc3C1-   OCCOCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1-   OCCOCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCN)Nc3c(C1)cncc3C1-   FC(F)(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCCC(F)(F)C3)Nc4c(C1)cncc4C1-   FC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCN3CCC(F)C3)Nc4c(C1)cncc4C1-   FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCn3nccn3)Nc4c(C1)cncc4C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCn3cnnc3)Nc4c(C1)cncc4C1-   FC1CCN(CCCCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C1)cncc4C1)CC1-   FC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCCN3CCC(F)(F)CC3)Nc4c(C1)cncc4C1-   OCCOCCOCCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCCOCCOCCOCCO)Nc3c(C1)cncc3C1-   CN(C)CCOC(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1-   C[N+](C)(C)CCNC(═O)COc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1-   FCOc1ccc2C(═CC(═O)Nc2c1OCC(═O)N3CCNCC3)Nc4c(C1)cncc4C1-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](Cc3c[nH]c4ccccc34)C(═O)O)Nc5c(C1)cncc5C1-   OC(═O)[C@H](Cc1c[nH]c2ccccc12)NC(═O)COc3c(OC(F)F)ccc4C(═CC(═O)Nc34)Nc5c(C1)cncc5C1-   OC(═O)[C@H](Cc1c[nH]c2ccccc12)NC(═O)CCCOc3c(OCF)ccc4C(═CC(═O)Nc34)Nc5c(C1)cncc5C1-   OC[C@H](NC(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H]([C@@H](C)O)C(═O)O)Nc3c(C1)cncc3C1-   OC(═O)C[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1)C(═O)O-   OC(═O)CNC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1-   NCCCC[C@H](NC(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1)C(═O)O-   OC(═O)CC[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N[C@@H](CCC(═O)N)C(═O)O)Nc3c(C1)cncc3C1-   NC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)OCCN(C)C)Nc3c(C1)cncc3C1-   C[C@@H](O)[C@H](NC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1)C(═O)O-   NC(═O)C[C@H](NC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3C1)C(═O)O-   CCCCN(C)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br-   FC1CCN(CCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C1)cncc4Br)C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCn3cccc3)Nc4c(C1)cncc4Br-   FCOc1ccc2C(═CC(═O)Nc2c1OCCCCn3ccnc3)Nc4c(C1)cncc4Br-   FC1CCN(CCCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C1)cncc4Br)C1-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCn3cnnc3)Nc4c(C1)cncc4Br-   FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCn3ncnn3)Nc4c(C1)cncc4Br-   COCCOCCOCCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br-   NCCCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br-   COCCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br-   FC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCCN3CCCCC3)Nc4c(C1)cncc4Br-   COCCOCCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br-   NC(═O)COc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)OCC[N+](C)(C)C)Nc3c(C1)cncc3Br-   CC(C)[C@H](NC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br)C(═O)O-   OC(═O)[C@H](Cc1ccc(O)cc1)NC(═O)COc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C1)cncc4Br-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)N[C@@H](C)C(═O)O)Nc3c(C1)cncc3Br-   OC(═O)[C@H](Cc1ccc(O)cc1)NC(═O)CCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(C1)cncc4Br-   OC(═O)C[C@H](NC(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br)C(═O)O-   OC(═O)CC[C@H](NC(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)OCC[N+](C)(C)C)Nc3c(C1)cncc3Br-   CN(C)CCCN(C)C(═O)CCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br-   CSCC[C@H](NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br)C(═O)O-   OC[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](Cc3ccc(O)cc3)C(═O)O)Nc4c(C1)cncc4Br-   CSCC[C@H](NC(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br)C(═O)O-   OC(═O)C[C@H](NC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br)C(═O)O-   NC(═O)CC[C@H](NC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(C1)cncc3Br)C(═O)O-   NC(═N)NCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br-   FC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCN3CCC(F)CC3)Nc4c(Br)cncc4Br-   FCOc1ccc2C(═CC(═O)Nc2c1OCCCCn3ccnn3)Nc4c(Br)cncc4Br-   COCCOCCOCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br-   CCCNCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br-   CCCCN(C)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br-   FC1CCN(CCCCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Br)cncc4Br)C1-   FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCn3ccnn3)Nc4c(Br)cncc4Br-   CCCCN(C)CCCCCCOc1c(OC)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br-   FC(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCCN3CCCCC3)Nc4c(Br)cncc4Br-   FC(F)(F)Oc1ccc2C(═CC(═O)Nc2c1OCCCCCCn3cccc3)Nc4c(Br)cncc4Br-   FCOc1ccc2C(═CC(═O)Nc2c1OCCCCCCn3ncnn3)Nc4c(Br)cncc4Br-   OC(═O)CNC(═O)COc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br-   COc1ccc2C(═CC(═O)Nc2c1OCC(═O)N[C@@H](C)C(═O)O)Nc3c(Br)cncc3Br-   OC(═O)[C@H](Cc1ccccc1)NC(═O)COc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Br)cncc4Br-   OC(═O)[C@H](Cc1ccc(O)cc1)NC(═O)COc2c(OC(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Br)cncc4Br-   COc1ccc2C(═CC(═O)Nc2c1OCCCC(═O)NCCN(C)C)Nc3c(Br)cncc3Br-   CN(C)CCCN(C)C(═O)CCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br-   OC(═O)[C@H](Cc1ccc(O)cc1)NC(═O)CCCOc2c(OC(F)(F)F)ccc3C(═CC(═O)Nc23)Nc4c(Br)cncc4Br-   OC[C@H](NC(═O)CCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)O-   OC[C@H](NC(═O)CCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCC(═O)N(C)CC[N+](C)(C)C)Nc3c(Br)cncc3Br-   CC(C)C[C@H](NC(═O)CCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)O-   OC(═O)[C@@H]1CCCN1C(═O)CCCCOc2c(OCF)ccc3C(═CC(═O)Nc23)Nc4c(Br)cncc4Br-   C[C@@H](O)[C@H]NC(═O)CCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)O-   CN(C)CCN(C)C(═O)CCCCCOc1c(OCF)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br-   C[C@H](NC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)O-   CC(C)[C@H](NC(═O)CCCCCOc1c(OC(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)O-   COc1ccc2C(═CC(═O)Nc2c1OCCCCCC(═O)N[C@@H](Cc3ccccc3)C(═O)O)Nc4c(Br)cncc4Br-   NC(═O)CC[C@H](NC(═O)CCCCCOc1c(OC(F)(F)F)ccc2C(═CC(═O)Nc12)Nc3c(Br)cncc3Br)C(═O)O-   COC1=CC═C(C(NC2=C(C)C═NC═C2C)=CC(N3)=O)C3=C1OCCCCCCN(CCO)-   COC1=CC═C(C(NC2=C(C)C═NC═C2C)=CC(N3)=O)C3=C1OCCCCCCN(CCO)CCO-   COC1=CC═C(C(NC2=C(C)C═NC═C2C)=CC(N3)=O)C3=C1OCCCCCCNCCCO-   COC1=CC═C(C(NC2=C(C)C═NC═C2C)=CC(N3)=O)C3=C1OCCCCCCN4CCNCC4-   COC1=CC═C(C(NC2=C(C)C═NC═C2C)=CC(N3)=O)C3=C1OCCCCCCN4CCCNCC4-   COC1=CC═C(C(NC2=C(C)C═NC═C2C)=CC(N3)=O)C3=C1OCCCCCCN4CCCN(C)CC4-   COC1=CC═C(C(NC2=C(C)C═NC═C2C)=CC(N3)=O)C3=C1OCCCCCCNCCCN(C)C-   COC1=CC═C(C(NC2=C(C)C═NC═C2C1)=CC(N3)=O)C3=C1OCCCCCCN4CCOCC4-   COC1=CC═C(C(NC2=C(C)C═NC═C2C1)=CC(N3)=O)C3=C1OCCCCCCN4CCCCC4-   COC1=CC═C(C(NC2=C(C)C═NC═C2C1)=CC(N3)=O)C3=C1OCCCCCCN4CCCC4-   COC1=CC═C(C(NC2=C(C)C═NC═C2C1)=CC(N3)=O)C3=C1OCCCCCCN(C)C-   COC1=CC═C(C(NC2=C(C)C═NC═C2C1)=CC(N3)=O)C3=C1OCCCCCCNCCO-   COC1=CC═C(C(NC2=C(C)C═NC═C2C1)=CC(N3)=O)C3=C1OCCCCCCN(C)CCO-   COC1=CC═C(C(NC2=C(C)C═NC═C2C1)=CC(N3)=O)C3=C1OCCCCCCN(CCO)CCO-   COC1=CC═C(C(NC2=C(C)C═NC═C2C1)=CC(N3)=O)C3=C1OCCCCCCNCCCO-   COC1=CC═C(C(NC2=C(C)C═NC═C2C1)=CC(N3)=O)C3=C1OCCCCCCN(C)CCCO-   COC1=CC═C(C(NC2=C(C)C═NC═C2C1)=CC(N3)=O)C3=C1OCCCCCCN4CCCNCC4-   COC1=CC═C(C(NC2=C(C)C═NC═C2C1)=CC(N3)=O)C3=C1OCCCCCCN4CCCN(C)CC4-   COC1=CC═C(C(NC2=C(C)C═NC═C2C1)=CC(N3)=O)C3=C1OCCCCCCNCCCN(C)C-   COC1=CC═C(C(NC2=C(C)C═NC═C2C1)=CC(N3)=O)C3=C1OCCCCCCN4CCN(C)CC4

The activity of the compounds in Examples 1-98 PDE4 inhibitors isillustrated in the following assay. The other compounds listed above,which have not yet been made and/or tested, are predicted to haveactivity in this assay as well.

PDE/AK Biological Activity Assay Protocol

Phosphodiesterases regulate the activity of the second messenger cyclicadenosine monophosphate (cAMP) by hydrolyzing cAMP to adenosinemonophosphate (AMP). We developed a coupled PDE/AK bioluminescenthigh-throughput assay to measure the activity of phosphodiesterases. Inthe PDE/AK assay, the AMP produced from the hydrolysis of cAMP byphosphodiesterase is converted to adenosine diphosphate (ADP) by thephosphotransferase activity of adenylate kinase (also known as ADK ormyokinase). Adenylate kinase will catalyze the conversion of 1 mole ofAMP and 1 mole of ATP into 2 moles of ADP. Thus the conversion of AMP toADP will result in the subsequent loss of ATP. The decrease in ATPconcentration can be monitored as light output using luciferase in areaction that requires ATP to produce light. The PDE/AK assay usesluciferase, which catalyzes the production of light from ATP present inthe reaction mix. The amount of emitted light is inversely proportionalto the level of AMP present in the reaction. Test compounds areincubated with the phosphodiesterases and phosphodiesterase inhibitorswill decrease the rate of cAMP hydrolysis and decrease the subsequentproduction of AMP. Thus phosphodiesterase inhibitors will decrease theconversion of ATP to ADP and result in the greatest emission of light.

Compounds may be screened for functional potency in in vitro biochemicalassays for their ability to inhibit the activity of phosphodiesterase(PDE) enzymes. A coupled PDE/AK assay was utilized to measure theinhibitory activity of compounds on PDE isoforms. The catalytic domainof PDE4B was fused to an amino-terminus hex-histidine affinity tag andpurified. PDE4B enzyme was incubated with compounds for 10 minutes.Cyclic AMP substrate, ATP and adenylate kinase were then added to thePDE enzyme mix and incubated for 45 minutes at room temperature. Acommercial ATP detection assay, Perkin Elmer's easyLite ATP detectionreagent, was then added to measure the relative amount of ATP present inthe reaction. After 10 minute incubation, the luminescent signal wasquantitated with either the Perkin Elmer Viewlux or Molecular DevicesAcquest or Analyst. Roflumilast and Rolipram are the positive controlsused in the assay.

The PDE/AK assay can be performed with any cAMP dependentphosphodiesterase, and can be performed in 96-, 384-, or 1536-wellplates. Unlike other phosphodiesterase activity assays, the PDE/AK assaydoes not require radioactive substrates, modified substrates, beads, orantibodies, which each have disadvantages. Specifically, the use ofradioactive substrates in a phosphodiesterase activity assay requiresspecial protocols for handling and waste disposal, and reducedthroughput. Modified substrates add the additional complexity ofpotentially altering the binding to the phosphodiesterase catalyticsite. Fluorescently modified substrates may cause fluorescence artifactsthat may interfere in the interpretation of assay results. The use ofbeads that selectively bind to either the cAMP or AMP may cause anadditional complexity in reagent handling. The use of antibodies thatselectively bind to either cAMP or AMP can be extremely costly with arelatively small signal to noise ratio. Therefore, the PDE/AK assayrepresents a simple, cost-effective alternative to known methods.

Additionally, the PDE/AK assay's mechanism offers advantages which makeit useful for comparison to other phosphodiesterase activity assays. Inconventional assays in which cAMP concentration is inverselyproportional to the output of bioluminescence (such as CambrexBiosciences's PDELight), phosphodiesterase catalyzes the hydrolysis ofcAMP to AMP that is subsequently converted to ATP, consumed by aluciferase enzyme, and results in an increased bioluminescent output. Aphosphodiesterase inhibitor prevents the hydrolysis of cAMP to AMP andconsequently results in a decreased bioluminescent output. However,compounds which exhibit luciferase inhibition activity would score as afalse positive for PDE inhibition in the conventional assay. Incontrast, the PDK/AK assay would not score luciferase inhibitors asfalse positive for PDE inhibition because inhibition of PDE activitywould result in increased bioluminescence. However, compounds that arecapable of inhibiting both PDE and luciferase would be false negatives.Compounds that inhibit adenylate kinase would score as false positivesin the PDE/AK assay. Use of both types of assay, and comparison of thedata from both, would yield a richer and more reliable data set.

Accordingly, contemplated herein is a method for the detection andquantitation of PDE inhibition which uses adenylate kinase coupled to anATP-depleting assay.

In certain embodiments, said method comprises the steps of:

-   -   1. A first incubation, of PDE, or an isolated isoform thereof,        with a compound to be tested;    -   2. Addition of ATP, cAMP, and AK substrates;    -   3. A second incubation of said PDE;    -   4. Coupling to a means for readout of ATP-depletion; and    -   5. Readout.

In further embodiments, said first incubation is for between about 5 andabout 15 minutes; in yet further embodiments, said first incubation isfor about 10 minutes.

In further embodiments, said second incubation is for longer than about30 minutes; in yet further embodiments, said sufficient length of timeis between about 30 minutes and about one hour; in even furtherembodiments, sufficient length of time is about 45 minutes.

In certain embodiments, said readout means is a luciferase assay. Infurther embodiments, said luciferase assay is a Perkin Elmer easyLiteassay.

In further embodiments, said readout is done on a machine for detectinga luminescent signal. In other embodiments, said machine is selectedfrom the group consisting of a Perkin Elmer Viewlux, a Molecular DevicesAcquest, and a Molecular Devices Analyst.

Results are shown below in Table 1.

Data reported as NT refers to the example having been not tested. It isexpected that these compounds when tested will be active and will haveutility similar to those that have been tested.

TABLE 1 Biological Activity PDE4 Enzyme IC50, + indicates <1 μM, Example− indicates >1 μM 1 + 2 NT 3 NT 4 NT 5 + 6 NT 7 NT 8 + 9 NT 10 NT 11 +12 + 13 + 14 + 15 + 16 + 17 NT 18 + 19 + 20 + 21 + 22 + 23 + 24 + 25 +26 + 27 + 28 + 29 + 30 + 31 + 32 + 33 + 34 + 35 + 36 + 37 + 38 + 39 NT40 NT 41 + 42 + 43 NT 44 + 45 + 46 NT 47 + 48 NT 49 + 50 + 51 + 52 +53 + 54 + 55 + 56 + 57 + 58 + 59 NT 60 NT 61 + 62 + 63 + 64 + 65 NT 66 +67 + 68 + 69 + 70 + 71 + 72 + 73 + 74 + 75 + 76 + 77 + 78 + 79 + 80 +81 + 82 + 83 + 84 + 85 + 86 + 87 + 88 + 89 NT 90 NT 91 NT 92 NT 93 NT94 + 95 + 96 + 97 + 98 +

In Vivo Assay Number One Lacrimal Gland Inflammation-Induced Dry Eye inRabbits

A more detailed description of the assay used herein may be found inNaglehout, T J et al. 2005, “Preservation of Tear Film Integrity andInhibition of Corneal Injury by Dexamethasone in a Rabbit Model ofLacrimal Gland Inflammation-Induced Dry Eye,” J. Ocular Pharm. Ther.,21:2. 139-148, the disclosure of which is hereby incorporated byreference as if written herein in its entirety.

Initiation of Dry Eye and Treatment

Rabbits (n=4/group) were randomized into treatment groups and dosedtopically BID with maxidex vehicle or test drug beginning one day priorto initiation of dry eye. Each rabbit received bilateral lacrimal glandinjections of saline or ConA (300 μg/30 μl) and topical ocular dosingwas continued BID throughout the study.

Corneal Staining

Desiccation was initiated 1-2 hours following lacrimal gland injectionby placing conscious rabbits in the environmental chamber (10-15%humidity/72° F.). Following 72 consecutive hours of exposure to this dryenvironment, the animals were anesthetized and sutures were placed ineach upper and lower eyelid and lifted to form a corneal/conjunctivalcup. Methylene blue dye (1 mL, 1% in dH₂O) was added to the cup forthree minutes and the excess removed by washing with 200 mL BSS®. Thecontralateral eye was then stained using the same procedure. Rabbitswere euthanized immediately following the staining procedure and theeyes were excised. The corneas were isolated with a trephine and the9.5-mm punch of the cornea was placed in 2 mL acetone/saturated sodiumsulfate (7:3, vol./vol.). Absorbance of the extracted dye was determinedat 660 nm.

Tear Breakup Time (TBUT)

TBUT was quantified in a separate group of treated animals. TBUT wasdetermined by instilling 5 μL sodium fluorescein into the cul de sac andmanually blinking the lids to distribute the fluorescein within the tearfilm. Under slit lamp observation, the eye was held open and the timewhereby one or more black spots or streaks appeared in the precornealtear film was recorded. The rabbits were euthanized 3 days followingConA injection.

Data reported as NT refers to the example having been not tested.

TABLE 2 In Vivo Activity Example Activity at Percent ConcentrationTested No. 1 × 10⁻⁶ 1 × 10⁻⁵ 1 × 10⁻⁴ 1 × 10⁻³ 1 × 10⁻² 1 × 10⁻¹ 1 1 NTNT NT NT Inactive Inactive Inactive 5 Inactive NT Inactive NT InactiveNT NT 8 Inactive NT Inactive NT Inactive NT NT

In Vivo Assay Number Two Guinea Pig Passive Conjunctival Anaphylaxis

Male Hartley VAF outbred guinea pigs were passively sensitized toovalbumin by a single OD subconjunctival injection of undiluted guineapig anti-ovalbumin antiserum 24 hours before OD topical challenge with500 μg ovalbumin in saline. Control animals were injected with salineonly and challenged with ovalbumin. To determine acute phase drugefficacy, 30 min after challenge animals were clinically scored by amasked observer for severity of signs of conjunctivitis based on astandard scale. Test compounds were administered as a 20 μL topical drop1 hour prior to challenge (QD), or 1 hour prior to challenge and again 8hours after challenge (BID). Positive control compound was dexamethasone(Dex) at 0.1% w/v, formulated similarly. Twenty-four hours afterchallenge, animals were euthanized and conjunctivae were harvested fordetermination of tissue eosinophil peroxidase (EPO) concentration as amarker of allergic inflammation. Homogenates of freshly collectedtissues were prepared by shaking the tissues in 2 mL round-bottom tubescontaining 0.5 mL of homogenization buffer (50 mM Tris HCl, pH 8.0, 6 mMKBr) and one 5-mm stainless steel bead on a Qiagen TissueLyser at 30 Hzfor 5 min. Homogenates were frozen and thawed once, then centrifuged at10,000 rpm for 5 min. EPO activity in supernatants was measured byreacting diluted homogenates with a solution of 6 mM o-phenylenediaminesubstrate and 8.8 mM H₂O₂ in homogenization buffer for 3 min. Thereaction was stopped with 4M H₂SO₄ and absorbances were measured at 490nm on a spectrophotometric plate reader. Total EPO in samples wascalculated from a standard curve of recombinant human EPO in each assay.EPO activity was normalized to total protein concentration (Pierce BCAassay) in supernatants. Background EPO activity was determined from theunsensitized, antigen-challenged control group. Percent inhibition wascalculated from the sensitized, antigen-challenged vehicle-treatedcontrol group in each experiment. Groups were compared by ANOVA withDunnett's or Tukey's post-hoc tests where appropriate with significanceassigned at the 95% confidence level.

Data reported as NT refers to the example having been not tested. It isexpected that these compounds when tested will be active and will haveutility similar to those that have been tested.

TABLE 3 In Vivo Activity Example 1 ++ 2 NT 3 NT 4 NT 5 ++ 6 NT 7 NT 8 ++9 NT 10 NT 11 + 12 NT 13 NT 14 + 15 ++ 16 ++ 17 NT 18 + 19 + 20 ++ 21 +22 + 23 NT 24 NT 25 + 26 + 27 ++ 28 ++ 29 NT 30 ++ 31 ++ 32 + 33 ++ 34NT 35 + 36 NT 37 + 38 ++ 39 NT 40 NT 41 NT 42 NT 43 NT 44 NT 45 + 46 NT47 NT 48 NT 49 + 50 + 51 ++ 52 ++ 53 NT 54 NT 55 ++ 56 NT 57 NT 58 NT 59NT 60 NT 61 NT 62 NT 63 NT 64 NT 65 NT 66 NT 67 NT 68 NT 69 NT 70 NT 71NT 72 ++ 73 ++ 74 NT 75 NT 76 NT 77 NT 78 NT 79 NT 80 NT 81 NT 82 NT 83NT 84 NT 85 NT 86 NT 87 NT 88 NT 89 NT 90 NT 91 NT 92 NT 93 NT 94 NT 95NT 96 NT 97 NT 98 NT ++: test compound at 0.01% w/v is statisticallyequivalent to Dex +: test compound at 0.1% w/v is statisticallyequivalent to Dex −: test compound at 0.1% w/v is not statisticallyequivalent to Dex

Solubility Protocol

About 5 mg of a compound was mixed with 500 μL of pH 7.4, 0.1 M sodiumphosphate buffer. The mixture was adjusted to the original pH of 7.4 andthen mixed overnight or longer via rotary mixing. The sample was checkedfor pH and then filtered through a 0.45 μm filter. If the pH driftedaway, the sample was adjusted to its original pH and mixed for at least15 minutes before filtration. The filtrate was analyzed using HPLC.

Data reported as NT refers to the example having been not tested. It isexpected that these compounds when tested will be active and will haveutility similar to those that have been tested.

TABLE 4 Solubility Solubility, pH 7.4, + indicates ≧1 mg/mL, Example −indicates <1 mg/mL 1 + 2 NT 3 NT 4 NT 5 + 6 NT 7 NT 8 NT 9 NT 10 NT 11 +12 + 13 NT 14 + 15 + 16 + 17 NT 18 + 19 + 20 + 21 + 22 + 23 NT 24 NT25 + 26 + 27 + 28 + 29 + 30 + 31 NT 32 + 33 + 34 NT 35 + 36 + 37 + 38 +39 NT 40 NT 41 + 42 + 43 NT 44 NT 45 + 46 NT 47 + 48 NT 49 + 50 + 51 +52 + 53 + 54 + 55 + 56 + 57 + 58 + 59 NT 60 NT 61 NT 62 + 63 NT 64 + 65NT 66 + 67 + 68 + 69 NT 70 + 71 + 72 + 73 + 74 + 75 + 76 − 77 − 78 NT 79NT 80 + 81 NT 82 NT 83 NT 84 NT 85 NT 86 NT 87 NT 88 NT 89 NT 90 NT 91NT 92 NT 93 NT 94 NT 95 NT 96 NT 97 NT 98 NT

Stability Protocol

About 3 mg of a compound was dissolved in 3 mL of acetonitrile/watermixture (50/50). 100 μL of the stock solution was added to 20 mL each of0.025 M pH 5.0 sodium acetate buffer (A5.0), 0.025 M pH 5.0 citratebuffer (C5.0) and 0.025 M pH 7.4 sodium phosphate buffer (P7.4). A twomL aliquot of each solution was kept in a glass vial equipped a caplined with Teflon. Two vials containing the solution were stored at 4°C. or −20° C. as control. Other aliquots were stressed at RT, 45° C. or75° C. for specified time check points, e.g. 1 day, 1 w, 2 w, 4 w, 8w,12 w. The stressed samples in duplicate were assayed against thecontrol using HPLC. The results were reported in % degradation.Preliminary shelf life (T90) was estimated assuming the rate of chemicaldegradation is double when the temperature is up 10° C.

Data reported as NT refers to the example having been not tested. It isexpected that these compounds when tested will be active and will haveutility similar to those that have been tested.

TABLE 5 Stability Stability, pH 7.4 + indicates ≧1 Year, Example −indicates <1 Year 1 + 2 NT 3 NT 4 NT 5 + 6 NT 7 NT 8 + 9 NT 10 NT 11 +12 NT 13 NT 14 + 15 + 16 + 17 NT 18 + 19 + 20 + 21 + 22 + 23 NT 24 NT 25NT 26 NT 27 NT 28 NT 29 NT 30 NT 31 NT 32 NT 33 NT 34 NT 35 + 36 NT 37NT 38 + 39 NT 40 NT 41 NT 42 NT 43 NT 44 NT 45 NT 46 NT 47 NT 48 NT 49NT 50 NT 51 NT 52 + 53 + 54 + 55 NT 56 + 57 + 58 + 59 NT 60 NT 61 + 62NT 63 NT 64 NT 65 NT 66 NT 67 NT 68 NT 69 + 70 NT 71 NT 72 NT 73 NT 74NT 75 NT 76 NT 77 NT 78 + 79 + 80 NT 81 NT 82 NT 83 NT 84 NT 85 NT 86 NT87 NT 88 NT 89 NT 90 NT 91 NT 92 NT 93 NT 94 NT 95 NT 96 NT 97 NT 98 NT

Compositions

The following are examples of compositions which may be used totopically deliver compounds disclosed herein, for example to the eye ornasal passages.

COMPOSITION EXAMPLE 1

Ingredients Concentration (w/v %) Compound of Formula (VI)  0.1% DibasicSodium Phosphate (Anhydrous)  0.5% Sodium Chloride 0.65% Benzalkoniumchloride 0.01% Sodium Hydroxide/Hydrochloric Acid For adjusting pH to7.0 ± 0.2 Purified Water q.s. to 100%

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound of structural Formula VI

or a salt thereof, wherein: R¹ and R² are independently selected fromthe group consisting of —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, carboxyalkyl,cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy,aminoalkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, ether,heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, andhydroxyalkyl, any of which may be optionally substituted; s is 1-8; G¹is selected from the group consisting of alkoxy, amino, amido, carbonyl,hydroxy, ether, an amino acid, and null; G² is selected from the groupconsisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl,heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an aminoacid, and null, any of which may be optionally substituted; G³ isselected from the group consisting of alkyl, alkoxy, amino, hydroxy,ether, carboxyl, hydroxamic acid, an amino acid, phosphonate,phosphoramide, and null, any of which may be optionally substituted; andR²⁰ and R²⁴ are independently selected from the group consisting ofhydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl,lower haloalkoxy, amino, and carboxyl.
 2. The compound as recited inclaim 1, wherein R²⁰ and R²⁴ are independently selected from the groupconsisting of hydrogen, halogen, and lower alkyl.
 3. The compound asrecited in claim 2, wherein: R¹ and R² are independently selected fromthe group consisting of —(CH₂)_(s)G¹G²G³, acyl, acylalkyl, C₁-C₁₀ alkyl,aminoalkyl, alkenyl, alkynyl, carboxyalkyl, heteroalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl,heteroaryl, and heteroaralkyl, any of which may be optionallysubstituted; and G² is selected from the group consisting of alkyl,alkoxy, amino, aryl, halo, heterocycloalkyl, heteroaryl,carboxylalkylamino, an amino acid, and null, any of which may beoptionally substituted with a substituent selected from the groupconsisting of lower alkyl, amino, alkylamino, alkylaminoalkyl,aminoalkylamino, aminoalkyl, hydroxylalkyl, hydroxylalkylamino,cycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl.
 4. The compoundas recited in claim 3, wherein R²⁰ and R²⁴ are independently selectedfrom the group consisting of halogen and lower alkyl.
 5. The compound asrecited in claim 4, wherein R² is lower alkyl.
 6. The compound asrecited in claim 5, wherein: R¹ is selected from the group consisting of—(CH₂)_(s)G¹G²G³, lower alkyl, cycloalkyl, cycloalkylalkyl, andheterocycloalkyl, any of which may be optionally substituted; s is 1-6;G¹ is selected from the group consisting of amino, amido, and null; G²is selected from the group consisting of alkoxy, amino, aryl, halo,heterocycloalkyl, and null; and G³ is selected from the group consistingof alkyl, carboxyl, and null, any of which may be optionallysubstituted.
 7. The compound as recited in claim 6, wherein R² ismethyl.
 8. The compound as recited in claim 7, wherein R¹ is—(CH₂)_(s)G².
 9. The compound as recited in claim 8, wherein s is
 6. 10.The compound as recited in claim 9, wherein R²⁰ and R²⁴ areindependently selected from the group consisting of halogen and methyl.11. The compound as recited in claim 10, wherein said halogen ischlorine.
 12. The compound as recited in claim 11, wherein G² isselected from the group consisting of amino and heterocycloalkyl. 13.The compound as recited in claim 12, wherein said heterocycloalkyl isselected from the group consisting of a five-, six-, and seven-memberedring containing one or two nitrogens.
 14. The compound as recited inclaim 13, wherein G² has a formula selected from the group consisting of

t is 1 or 2; w is 0 or 1; R²⁵ and R²⁶ are independently selected fromthe group consisting of hydrogen, methyl, —(CH₂)_(x)OH, and—(CH₂)₃N(CH₃)₂; x is 2 or 3; and R²⁷ is selected from the groupconsisting of hydrogen and methyl.
 15. The compound as recited in claim14, wherein G² has a formula selected from the group consisting of

R²⁵ and R²⁶ are independently selected from the group consisting ofmethyl and —(CH₂)_(x)OH.
 16. The compound as recited in claim 15,wherein R²⁰ and R²⁴ are each chlorine.
 17. The compound as recited inclaim 16, wherein G² is


18. The compound as recited in claim 17, wherein R²⁷ is methyl.
 19. Thecompound as recited in claim 18, wherein t is
 1. 20. The compound asrecited in claim 18, wherein t is
 2. 21. The compound as recited inclaim 16, wherein G² is


22. The compound as recited in claim 16, wherein G² is —NR²⁵R²⁶.
 23. Thecompound as recited in claim 22, wherein: R²⁵ is methyl; and R²⁶ is—(CH₂)_(x)OH.
 24. The compound as recited in claim 23, wherein x is 2.25. The compound as recited in claim 15, wherein R²⁰ and R²⁴ are eachmethyl.
 26. The compound as recited in claim 25, wherein G² has aformula selected from the group consisting of


27. The compound as recited in claim 26, wherein G² is —NR²⁵R²⁶.
 28. Thecompound as recited in claim 27, wherein R²⁵ and R²⁶ are each methyl.29. The compound as recited in claim 26 wherein G² is


30. A compound selected from the group consisting of Examples 1 to 98.31. A compound as recited in claim 1 for use as a medicament.
 32. Acompound as recited in claim 1 for use in the manufacture of amedicament for the prevention or treatment of a disease or conditionameliorated by the inhibition of PDE4.
 33. The compound as recited inclaim 32, wherein said PDE4 is the PDE4B subtype.
 34. A pharmaceuticalcomposition comprising a compound as recited in claim 1 together with apharmaceutically acceptable carrier.
 35. A method of inhibition of PDE4comprising contacting PDE4 with a compound as recited in claim
 1. 36. Amethod of treatment of a PDE4-mediated disease comprising theadministration of a therapeutically effective amount of a compound asrecited in claim 1 to a patient in need thereof
 37. The method asrecited in claim 36 wherein said PDE4-mediated disease is an ophthalmicdisease.
 38. The method as recited in claim 37, wherein said ophthalmicdisease is selected from the group consisting of allergicconjunctivitis, dry eye, glaucoma, corneal neovascularization, opticneuritis, Sjogren's syndrome, retinal ganglion degeneration, ocularischemia, retinitis, retinopathy, uveitis, ocular photophobia, andinflammation and pain associated with acute injury to the eye tissue.39. A method of treatment of allergic conjunctivitis to a patient inneed thereof comprising the administration of a compound selected fromthe group consisting of Examples 15, 16, 26, 30, 35, and
 38. 40. Amethod for achieving an effect in a patient comprising theadministration of a therapeutically effective amount of a compound asrecited in claim 1 to a patient, wherein the effect is selected from thegroup consisting of treatment of nasal allergies, treatment of ocularallergies, ophthalmic disorders, treatment of dry eye, and analgesia ofeye tissue.